JP2020530007A - 2-PMPA prodrug for health tissue protection during PSMA-targeted cancer imaging or radiation therapy - Google Patents

Abstract

Disclose the use of a class of 2-PMPA prodrugs that alter the tissue distribution of 2-PMPA for non-prostate tissue. The prodrugs of the present disclosure are selectively distributed to healthy tissues, including the kidneys, lacrimal glands, and salivary glands, which represent off-target binding and toxic sites for PSMA-targeted prostate cancer imaging agents and therapies. Therefore, 2-PMPA prodrugs can be used for pretreatment of PSMA-targeted cytotoxicity or radiation therapy, binding to the kidneys and salivary glands, and shielding from them.

Description

Cross-reference to related applications

This application claims the benefit of US Provisional Application No. 62 / 484,219 filed April 11, 2017, which is incorporated herein by reference in its entirety.

Federal-funded research or development This invention was approved by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) R01 CA161056- Made under 01 with government support. The government has certain rights in the present invention.

Background prostate cancer cells, as well as endothelial cells in angiogenesis of multiple other solid tumors, significantly overexpress prostate-specific membrane antigens (PSMA), membrane tethers (also known as membrane anchorages, membrane anchorages, etc.) ( Kasperzyk et al., 2013). Overexpression of PSMA has been shown to correlate with aggressive tumors, metastatic disease, and poor prognosis in prostate cancer patients (Perner et al., 2007). Successful efforts have been made to target PSMA with radiolabeled or cytotoxic drug conjugate biologics (biologic) and small molecule ligands for imaging prostate cancer tumors (Bouchelouche et al.) , 2016; Ceci et al., 2017; Haberkorn et al., 2016; Kratochwil (also known as Kratochiwill, Kratovville, etc.), 2016; Maurer et al., 2016) or targeted chemotherapy or radiation therapy (Bouchelouche) , 2016; Ceci et al., 2017; Haberkorn et al., 2016; Kratochwil et al., 2016; Maurer et al., 2016; and Pilari et al., 2016) and several clinical trials are underway. However, in addition to prostate cancer and proliferative endothelial cells, normal tissue also expresses non-CNS-expressing PSMA in the kidneys, lacrimal glands, and salivary glands at the highest density. Therefore, these tissues represent areas of interference (for PSMA-expressing cancer imaging) or dose-limiting sites of toxicity (for PSMA-targeted cancer treatment) (Kratochwil et al., 2015).

Highly selective and well tolerated PSMA inhibitor (also known as PSMA inhibitor) 2- (phosphonomethyl) pentanedioic acid (2-PMPA) in an attempt to reduce exposure to healthy tissue during PSMA targeting therapy Was evaluated for their ability to block radioligand uptake through direct competitive displacement in the salivary glands and kidneys (Kratochwil et al., 2015; Chatalic et al., 2016). .. In one study, co-injection of 2-PMPA (0.01 mg) with ¹⁷⁷ Lu-PSMA I & T (100MBq) reduced the absorbed dose to the kidney by 83% in mice with human cancer xenografts expressing PSMA. Nephrotoxicity was weakened after 3 months (Chatalic et al., 2016). Although promising, these results show that 2-PMPA also suppressed tumor uptake of radiotherapeutic agents (radiotherapeutic) by more than 50%, thus not prompting clinical trials and mice receiving radiotherapy agents alone. Tumor growth was accelerated and overall survival was significantly reduced compared to (Chatalic et al., 2016). Similar results were obtained when 2-PMPA was paired with ¹²⁵ I-MIP-1095 (Kratochwil et al., 2015). Previously attempted mitigation strategies for salivary glands also failed (Taieb et al., 2018), which included concomitant treatment with 2-PMPA to suppress PSMA-specific uptake (Kratochwil et al., 2015). These findings are associated with preclinical pharmacokinetic data showing little or no penetration into the salivary glands, probably due to its high polarity and poor tissue penetration when 2-PMPA is given as a parent. Match (Majer et al., 2016). Therefore, 2-PMPA provided an important proof of concept for the shielding approach, but co-treatment with this molecule would have significantly improved the therapeutic index of PSMA-targeted therapy for salivary gland / kidney replacement and tumor uptake. I couldn't balance between.

In some embodiments, the subject matter of the present disclosure provides methods for preventing or reducing the accumulation of prodrug-specific membrane antigen (PSMA) imaging or therapeutic agents in off-target non-cancerous tissue, the method. For subjects treated with PSMA-targeted imaging or therapeutic agents, the prodrug of 2- (phosphonomethyl) pentanedioic acid (2-PMPA) is off-targeted to prevent or reduce binding of the agent to non-cancerous tissue. It involves applying in an amount effective to be done. In contrast to 2-PMPA, the 2-PMPA prodrugs of the present disclosure show unexpected preferential distribution in healthy non-cancerous tissues, including kidney and salivary glands, where they interfere with PSMA-targeted agents. Or represents dose limiting toxicity. In doing so, the methods of the present disclosure extend the therapeutic range of PSMA-targeted therapies, reduce the risk of salivary gland and renal toxicity, and possibly allow for more treatment cycles initiated early in the course of the disease. ..

In some embodiments, 2-PMPA prodrugs include compounds of formula (I) or formula (II):
During the ceremony:
Each R ₁ , R ₂ , R ₃ , and R ₄ are H, alkyl, Ar,-(CR ₅ R ₆ ) _n -Ar,-(CR ₅ R ₆ ) _n -OC (= O) -R ₇ , -(CR ₅ R ₆ ) _n -C (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OC (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OR ₇ ,-(CR ₅ R ₆ ) CR ₅ R ₆ ) _n -O-[(CR ₅ R ₆ ) _n -O] _m -R ₇ ,-(CR ₅ R ₆ ) _n -Ar-OC (= O) -R ₇ , -Ar-C ( = O) -O- (CR ₅ R ₆ ) _n -R ₇ ,-(CR ₅ R ₆ ) _n -NR ₈ R ₉ , and-(CR ₅ R ₆ ) _n -C (= O) -NR ₈ R chosen independently from the group consisting of _9; wherein: n is an integer from 1 to 20; m is an integer from 1 to 20; each R ₃ 'and R _4' is independently H or alkyl Yes; each R ₅ and R ₆ are independently selected from the group consisting of H, alkyl, and alkylaryl; each R ₇ is independently linear or branched alkyl; Ar is aryl, substituted aryl, hetero It is aryl or substituted heteroaryl; and R ₈ and R ₉ are independently H or alkyl, respectively; and include pharmaceutically acceptable salts thereof.

In a particular embodiment, the compound of formula (I) is:
Is.

In other aspects, the subject matter of the present disclosure provides a method for reducing salivary gland damage in patients undergoing PSMA-targeted therapy for cancer, providing therapeutically effective amounts of 2-PMPA prodrugs to the patient. Including giving.

In certain embodiments, salivary gland injury causes side effects selected from the group consisting of dry mouth, concentrated saliva, reduced saliva, stomatitis, hoarseness, dysphagia, taste loss, and combinations thereof.

In yet another aspect, the subject matter of the present disclosure provides a method for reducing kidney damage in patients undergoing PSMA-targeted therapy for cancer, providing therapeutically effective amounts of 2-PMPA prodrugs to the patient. Including giving.

Certain aspects of the subject matter of the present disclosure mentioned above are addressed in whole or in part by the subject matter of the present disclosure, and other aspects are most here in the context of the accompanying examples and figures. When adopted to explain well, it will become apparent as the explanation progresses.

Having described the subject matter of the present disclosure in general terms in this way, the accompanying drawings will be referred to next, but they are not necessarily drawn to scale and are as follows:
It is shown that the Tris-POC-2-PMPA prodrug delivered significantly higher 2-PMPA concentrations to the kidneys of nude mice. Compared to equimolar doses of 2-PMPA, Tris-POC-2-PMPA (5 mg / kg, ip) increased 2-PMPA levels in the kidney by more than 20-fold. 2A and 2B show that, in contrast to the 2-PMPA prodrugs of the present disclosure, a similar prodrug of the alternative urea-based PSMA ligand, ZJ-43, compared to the parental administration of ZJ-43. (Fig. 2A), showing no increased distribution to mouse kidneys or salivary glands (Fig. 2B). 3A and 3B show Tris-POC-2-PMPA treatment (Figure 3A) compared to equimolar 2-PMPA treatment in prostate cancer tumor-bearing mice. It is shown that 3B) results in significantly increased renal and salivary gland delivery of 2-PMPA, and improved kidney: tumor and saliva: tumor ratio. Tail veins of either 2-PMPA or Tris-POC-2-PMPA (3 mg / kg or molar equivalent, iv) to NSG mice with subcutaneous xenografts of human C4-2 prostate cancer cells Concentrations of 2-PMPA in the prostate, tumor, salivary gland, and kidney were measured at multiple time points after dosing. Figures 4A, 4B, 4C, and 4D are presented as baseline PET imaging (maximum intensity projections) of nontumor-bearing mice 1 hour after injection of 20 MBq of ⁶⁸ Ga-PSMA-617. ) (Fig. 4A) and quantification of renal uptake by mSUV (Fig. 4C). The same animals were reimaging one hour after the subsequent injection of Tris-POC-2-PMPA (0.5 mg / kg BW) (Fig. 4B). Tracer concentrations were then quantified in the kidney by mSUV (Fig. 4D). Figures 5A, 5B, 5C, and 5D show kidneys and mSUV-based kidneys and mSUV-carrying mice carrying LNCaP tumor xenografts (left shoulder) 1 hour after injection of ⁶⁸ Ga-PSMA-617. Quantification of tumor uptake (Fig. 5C) is shown. The same animals were reimaged an additional hour after subsequent injections of different doses of Tris-POC-2-PMPA (or sarin (salt solution) as a control) (Fig. 5B), followed by quantified tumor and renal uptake. (Fig. 5D). Figures 6A, 6B, 6C, and 6D show the biodistribution of ⁶⁸ Ga-PSMA-617 1h pi and pre-medication of Tris-POC-2-PMPA presented as a maximal projection in healthy subjects. Without pre-dosing) (Fig. 6A, left) or after its Tris-POC-2-PMPA (Fig. 6A, right). Without pre-medication, renal uptake increased over time, whereas the temporal activity curve showed renal binding by pre-medication with 0.05 mg / kg BW Tris-POC-2-PMPA 10 minutes prior to PET-tracer. Means saturation of (Fig. 6C). A similar effect was observed for the temporal activity curve of the parotid gland (Fig. 6D). Thin cortical slices through the kidney of the subject without or with pre-medication (Figure 6B, top) or with it (Figure 6B, bottom) showed that saturation of the PSMA binding site was physiologically expressed in the proximal tubule. Means, on the contrary, it is located in the renal cortex. Although not bound by any particular theory, this observation is believed to indicate the mechanism of action proposed for the methods of the present disclosure. ⁶⁸ Ga-PSMA-617 An individual comparison of 1 h pi in the body distribution is shown, with or without pre-medication presented as a maximal projection in the prostate cancer patient of Tris-POC-2-PMPA. When pretreated with Tris-POC-2-PMPA, patients showed similar tracer uptake in tumors, but renal and salivary gland uptake was significantly reduced. and Tris-POC-2-PMPA Tris for biodistribution and absorbed radiation to organs or metastases after administration of ¹⁷⁷ Lu-PSMA-617 in prostate cancer patients compared to historical controls receiving radiation therapy without PMPA -POC-2-PMPA Shows the effect of pretreatment. Based on a positive diagnostic PET scan, the two patients received Tris-POC-2-PMPA (10 mg, iv) 15 minutes prior to infusion with ¹⁷⁷ Lu-PSMA-617. Pretreatment of Tris-POC-2-PMPA results in 45% uptake of radiotherapy material in the parotid, submandibular, and kidney compared to historical controls from the same facility (Kratochwil et al., 2016). It decreased by only 75%. In contrast, pretreatment with Tris-POC-2-PMPA had little or no effect on the dose to metastases, all values were within the standard deviation of historical control, and, decisively, therapeutic efficacy. It exceeded the absorbed dose values reported to result in (Kratochwil et al., 2016).

The patent or application file contains at least one drawing made in color. A copy of this patent or patent application publication with color drawings will be provided by the institution upon request and payment of the required fee.

Detailed Description The subject matter of the present disclosure is then described further in full with reference to the accompanying drawings, which show some, but not all, embodiments of the present invention. Similar numbers refer to similar elements throughout. The subject matter of this disclosure may be embodied in many different forms and should not be construed as being limited to the embodiments described herein; rather, these embodiments are the legal to which this disclosure applies. Provide to meet the requirements. In fact, many modifications and other embodiments of the subject matter of the present disclosure described herein are described above and in the relevant figures to those skilled in the art to which the subject matter of the present disclosure relates. You will think of benefiting from the teachings presented. Therefore, it is understood that the subject matter of the present disclosure is not limited to the particular embodiments disclosed and that modifications and other embodiments are intended to be within the scope of the appended claims. Should be.
I. 2-PMPA prodrug for healthy tissue protection during PSMA-targeted cancer imaging or radiation therapy

Prostate-specific membrane antigen (PSMA), also known as GCPII (carboxypeptidase II) and FOLH1, hydrolyzes N-acetylated aspartate-glutamic acid (NAAG) to N-acetylaspartate (NAA) and glutamate. It is a metallopeptidase that catalyzes and sequentially cleaves terminal glutamate moyet from polyglutamate folic acid. One of the most potent, selective and effective PSMA inhibitors is 2- (phosphonomethyl) pentanedioic acid (2-PMPA). However, 2-PMPA is a highly polar compound with multiple carboxylates and zinc binding groups, and it has negligible oral availability and inadequate tissue penetration. Therefore, in most cases it must be administered intravenously, intraperitoneally, or topically to achieve the desired effect. This fact limits its potential use as a therapeutic agent.

The subject matter of this disclosure, in part, demonstrates that certain prodrugs of 2-PMPA (see, Mager et al., 2016) unexpectedly accumulated in the kidneys and salivary glands when applied to animals. .. Importantly, some of these prodrugs, when applied to mice carrying prostate cancer xenografts, to the salivary glands and kidneys of rodents, 3 and 57 times, respectively, compared to tumors, 2 -Showed priority delivery of PMPA. We do not want to be bound by any particular theory, but given this profile, the administration of 2-PMPA prodrugs does not interfere with the uptake of radioligands in the target tumor tissue, but these "off". It was believed that subsequent PSMA radioligand binding to the "target" non-cancerous tissue could be prevented. Specific prodrugs of 2-PMPA are disclosed herein, but those of ordinary skill in the art (also referred to as those skilled in the art) show differential accumulation in the kidneys and salivary glands. It will be appreciated that the prodrugs, and any GCPII inhibitors, could have been suitable for use by the methods of the present disclosure.

The subject matter of this disclosure demonstrates the effectiveness of this approach. For example, in mice carrying prostate tumors, healthy human volunteers, and prostate cancer patients, administration of 2-PMPA prodrug prior to administration of PSMA radioligand favors binding of radioligand in the kidney and salivary glands. Replaced successfully, but tumor uptake was preserved. Therefore, the 2-PMPA prodrugs of the present disclosure are clinically used as pretreatment agents to improve the specificity of PSMA-targeted imaging (also referred to as imaging) agents and radiotherapy and reduce their toxicity. It has the potential to be used as a target.

In more detail, the subject matter of this disclosure is a new use for a class of 2-PMPA prodrugs that alter the tissue distribution of 2-PMPA to non-cancerous tissues and improve 2-PMPA delivery to healthy organs. provide. The prodrugs of the present disclosure are preferentially distributed in the kidney, lacrimal gland, and salivary gland, which represent off-target binding and toxic sites of PSMA-targeted prostate cancer imaging agents and radiation therapy.

Therefore, the subject matter of the present disclosure provides unexpected insights into PSMA small molecule inhibitors with enhanced accumulation in non-cancerous tissues (eg, kidney, lacrimal gland, and salivary gland). Animal data, which have been identified in humans, show that the 2-PMPA prodrugs of the present disclosure, in combination with PSMA-targeted imaging or radiation therapy, have non-selective and potential dose-limiting toxicity, respectively. Indicates that it can be reduced.

Therefore, in some embodiments, the subject matter of the present disclosure is to prevent or reduce the accumulation of prostate-specific membrane antigen (PSMA) theranostic agents in off-target (also referred to as non-target) non-cancerous tissues. The method provides a prodrug of 2- (phosphonomethyl) pentanedioic acid (2-PMPA) to off-target non-cancerous tissue for subjects treated with PSMA theranostics. Includes application in an amount effective to prevent or reduce binding of the PSMA ceranostic agent. In such embodiments, the off-target tissue is shielded from radiotherapeutic agents.

In some embodiments, the 2-PMPA prodrug is administered in combination with a PSMA theronotic agent. By "in combination", one or more (also referred to as one or more) of the compounds of the present disclosure may be administered with one or more therapeutic agents, either prior, simultaneous, sequential, or a combination thereof. means. Thus, a cell or subject may apply one or more compounds and one or more therapeutic agents of the present disclosure at the same time (so-called, simultaneously) or at different times (so-called, continuously, in any order, so-called before or after. , On the same day, or on different days), as long as the effect of the combination of both agents is achieved in the cell or subject. When applied sequentially, the agents can be applied to each other within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer. In other embodiments, the agents applied consecutively can be applied to each other within 1, 5, 10, 15, 20 or longer days. When one or more compounds of the present disclosure and one or more therapeutic agents are applied simultaneously, they are applied to the cells as separate pharmaceutical compositions containing either one or more of the compounds of the present disclosure or one or more therapeutic agents, respectively. Alternatively, they can be applied to a subject, or they can be contacted with cells as a single composition, or they can be applied to a subject as a single drug composition comprising both agents. In certain embodiments, the 2-PMPA prodrug is applied to the subject prior to applying a PSMA cellonotic agent or imaging agent (also referred to as a contrast agent). In such an embodiment, the subject is "pretreated" with a 2-PMPA prodrug. In other embodiments, the 2-PMPA prodrug is administered to the subject at the same time as the PSMA cellonostic or imaging agent.

In certain embodiments, the off-target tissue is in an organ selected from the group consisting of kidneys, lacrimal glands, and salivary glands.

In certain embodiments, the PSMA cellonotic agent is selected from the group consisting of CTT1403, MIP-1095, PSMA-11, PSMA-617, PSMA-R2, and PSMA I & T. Those of normal skill in the art are those who have other radiolabeled PSMA cellonostic agents, in fact, any PSMA targeting agent, a binding site or a biological or small molecule known in the art. You will recognize that it will be suitable for use in the methods of this disclosure regardless.

Representative prodrugs of 2-PMPA suitable for use with the methods of the present disclosure include PRODRUGS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITOR (prostate-specific membrane antigen (PSMA) inhibitors) to Slusher et al. (Prodrugs), including those disclosed under International PCT Patent Application Publication No. WO2016022827A1 and published on February 11, 2016, which are incorporated herein by reference in their entirety.

Table 1 provides the structure of a typical 2-PMPA prodrug.

In yet other embodiments, fine-tuning the rate of hydrolysis can be assessed by a combination of POC and methyl-substituted POC, as exemplified by the following compounds:

Further directions for 2-PMPA prodrugs include the following approaches, including phenyl esters that are even more effortlessly hydrolyzable; anhydrides, and dioxolone esters that employ paraoxonase for biotransformation:

In addition, the following dioxolone esters and 2-PMPA anhydride prodrugs are possible:

Further examples of alternative carboxyester prodrugs for 2-PMPA include:

More specifically, in some embodiments, 2-PMPA prodrugs include compounds of formula (I) or formula (II):
During the ceremony:
Each R ₁ , R ₂ , R ₃ , and R ₄ are H, alkyl, Ar,-(CR ₅ R ₆ ) _n -Ar,-(CR ₅ R ₆ ) _n OC (= O) -R ₇ ,- (CR ₅ R ₆ ) _n -C (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OC (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OR ₇ ,-(CR ₅ R ₆ ) ₅ R ₆ ) _n -O-[(CR ₅ R ₆ ) _n -O] _m -R ₇ ,-(CR ₅ R ₆ ) _n -Ar-OC (= O) -R ₇ , -Ar-C (= O) -O- (CR ₅ R ₆ ) _n -R ₇ ,-(CR ₅ R ₆ ) _n -NR ₈ R ₉ , and-(CR ₅ R ₆ ) _n -C (= O) -NR ₈ R ₉ Selected independently from the group consisting of;
During the ceremony:
n is an integer from 1 to 20;
m is an integer from 1 to 20;
Each R ₃ 'and R _4' are independently H or alkyl;
Each R ₅ and R ₆ was selected independently from the group consisting of H, alkyl, and alkylaryl;
Each R ₇ is linear or branched alkyl independently;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and
R ₈ and R ₉ are independently H or alkyl; and include pharmaceutically acceptable salts thereof.

As herein further defined below, "alkyl" represented by R ₁ -R ₉ and R ₃ 'and R _4' of Formula (I) and formula _{(II), C 1, C 2, C} 3 , C ₄ , C ₅ , C ₆ , C ₇ , or C ₈ linear or branched alkyl, C _1-4 substituted or unsubstituted alkyl in some embodiments, C _1-6 substituted in some embodiments. Or unsubstituted alkyl, in some embodiments can be C _1-8 alkyl substituted or unsubstituted alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Includes sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, and others of the same type, each of which Can contain one or more substitution components (substitutents). Representative substituent groups are not limited to alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate (sulfate), cyano, Includes mercapto, and alkylthio.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compound of formula (I)
Is.

In certain embodiments, the compounds of formula (I) are:
Selected from the group consisting of.

In certain embodiments, the compound of formula (II) is
Is.

In certain embodiments, the compound of formula (II) is
Is.

In other embodiments, the subject matter of the present disclosure provides a method for reducing salivary gland damage in patients receiving PSMA-targeted therapy for cancer, which comprises a therapeutically effective amount of a 2-PMPA prodrug. Includes giving to the patient.

In certain embodiments, salivary gland damage includes dry mouth, thickened saliva (also referred to as thickened saliva), decreased saliva, stomatitis, hoarseness, difficulty swallowing (also referred to as trouble swallowing, dysphagia, etc.), loss of taste. , And a combination thereof causes side effects selected from the group.

In yet another embodiment, the subject matter of the present disclosure provides a method for reducing kidney damage in patients undergoing PSMA-targeted therapy for cancer, which is a therapeutically effective amount of a 2-PMPA prodrug. Is included in applying to the patient.

In certain embodiments, 2-PMPA prodrugs of methods for reducing salivary gland and / or kidney damage include compounds of formula (I) or formula (II):
During the ceremony:
Each R ₁ , R ₂ , R ₃ , and R ₄ are H, Alkyl, Ar,-(CR ₅ R ₆ ) _n -Ar,-(CR ₅ R ₆ ) _n -OC (= O) -R ₇ , -(CR ₅ R ₆ ) _n -C (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OC (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OR ₇ ,-(CR ₅ R ₆ ) CR ₅ R ₆ ) _n -O-[(CR ₅ R ₆ ) _n -O] _m -R ₇ ,-(CR ₅ R ₆ ) _n -Ar-OC (= O) -R ₇ , -Ar-C ( = O) -O- (CR ₅ R ₆ ) _n -R ₇ ,-(CR ₅ R ₆ ) _n -NR ₈ R ₉ , and-(CR ₅ R ₆ ) _n -C (= O) -NR ₈ R Selected independently from the group of ₉ ;
During the ceremony:
n is an integer from 1 to 20;
m is an integer from 1 to 20;
Each R ₃ 'and R _4' are independently H or alkyl;
Each R ₅ and R ₆ was selected independently from the group consisting of H, alkyl, and alkylaryl;
Each R ₇ is linear or branched alkyl independently;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and
R ₈ and R ₉ are independently H or alkyl; and include pharmaceutically acceptable salts thereof.

In a more specific embodiment, the 2-PMPA prodrug is:
Selected from the group consisting of.

In certain embodiments, the agents for PSMA-targeted imaging or treatment are 117Lu-PSMA-617, 131I-MIP-1095, 177Lu-PSMA-I & T, 177Lu-PSMA-R2, 225Ac-PSMA-617, 227Th-PSMA- It is selected from the group consisting of ADC, CTT1403, CTT1700, 68Ga-PSMA-11, 18F-DCFPyL, CTT1057, 68Ga-PSMA-R2, and 68Ga-PSMA-617.

In some embodiments, the PSMA-targeted therapeutic substance is a radiotherapeutic substance applied in a cumulative amount from about 3 GBq to about 100 GBq. In certain embodiments, the PSMA-targeted radiotherapeutic material is applied in cumulative amounts from about 52 GBq to about 100 GBq.

In some embodiments, the PSMA-targeted therapeutic agent and 2-PMPA prodrug are administered for about 1 to about 15 treatment cycles. In certain embodiments, the PSMA-targeted therapeutic agent and 2-PMPA prodrug are administered for about 6 to about 15 treatment cycles.

In certain embodiments, the patient has never previously been treated for cancer. In an even more certain embodiment, the cancer is prostate cancer.
II. Drug composition and management

In another aspect, the present disclosure relates to a compound of formula (I), or a compound of formula (II) alone or in combination with a pharmaceutically acceptable excipient, with one or more additional therapeutic agents. Provided are a drug composition containing in combination. Those skilled in the art will recognize that the drug composition contains pharmaceutically acceptable salts of the above compounds.

For therapeutic and / or diagnostic applications, the compounds of the present disclosure can be dispensed, including systemic and topical or localized, for a wide variety of modes of control. Technology and dispensing of ^{generally, Remington: (. 20 th ed} ) The Science and Practice of Pharmacy Lippincott, Williams & Wilkins (2000) ( Remington: The Science and Practice of Pharmaceutical (20th ed.) Lippincott, Williams & Wilkins (2000 )) Can be found.

The compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages from 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. The non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is applied, the subject being treated, the weight of the subject being treated, and the priority and experience of the attending physician.

Pharmaceutically acceptable salts are usually well known to those of ordinary skill in the art, and, by way of example, but not limited to acetates, benzenesulfonates, vesylates, benzoates, hydrogen carbonates (heavy). Carbonate), hydrogen tartrate (heavy tartrate), bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edicylate, estrato, esylate, fumarate, gluceptate, glucon Acids, Glutamines, Glycolylarsanilate, Hexyl Resorcinato, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isetionate, Lactate, Lactobionate, Appleate , Maleate, Mandelate, Mecilate, Mucate, Napsilate, Nitrate, Pamoart (Embonate), Pantothenate, Phosphate / Diphosphate, Polygalacturonate, Salicylate, Stearate, It may include basic acetate, oxalate, sulfate, tannate, tartrate, or theocrate. Other pharmaceutically acceptable salts include, for ^{example, Remington: (. 20 th ed} ) The Science and Practice of Pharmacy Lippincott, can be found in Williams & Wilkins (2000). Pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsilate, pamoart. (Embonate), phosphates, salicylates, sulphates, sulfates, or tartrates.

Depending on the particular condition being treated, such agents may be dispensed into liquid or solid dosage forms and applied systemically or topically. The agent may be delivered, for example, in a timed-or sustained-low release form, as is known to those skilled in the art. Of the preparation and management ^{techniques, Remington: (. 20 th ed} ) The Science and Practice of Pharmacy Lippincott, can be found in Williams & Wilkins (2000). Suitable routes include oral, oral, intra-salivary, inhalation spray sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, intramuscular , Sublingual, intramedullary injection, and intrathecal, direct intraventricular (also referred to as direct intraventricular), intravenous, intra-articular, intra-sternal, intra-synovial, It may include intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection or other delivery modes.

For injection, the agents of the present disclosure may be dispensed and diluted in aqueous solution, such as in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological salt solution buffer. .. For such transmucosal application, a penetrant suitable for the penetrating barrier is used in the preparation. Such penetrants are generally known in the art.

The use of a pharmaceutically acceptable Inactive Carrier for dispensing the compounds disclosed herein for the practice of the present disclosure to dosages suitable for global administration is within the scope of the present disclosure. With proper selection of carriers and proper manufacturing practices, the compositions of the present disclosure, particularly those prepared as a solution, can be administered parenterally, such as by intravenous injection. The compound can be easily dispensed into a suitable dosage for oral administration using a pharmaceutically acceptable carrier well known in the art. Such carriers are tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and others for the compounds of the present disclosure to be orally ingested by the subject being treated (eg, patient). Allows to be dispensed as a kind and so on.

For nasal or inhalation delivery, the agents of the present disclosure may also be dispensed by methods known to those skilled in the art and, for example, without limitation, examples of solubilization, dilution, or dispersion of substances, eg, Salt solutions, preservatives, such as those such as benzyl alcohol, absorption enhancers, and fluorocarbons and the like may be included.

Pharmaceutical compositions suitable for use in the present disclosure include compositions containing an active ingredient in an amount effective to achieve its intended purpose. The determination of the effective amount is well within the ability of a skilled person in the art, especially in light of the detailed disclosure provided herein.

These drug compositions may include suitable pharmaceutically acceptable carriers, including excipients and auxiliaries, in addition to the active ingredients, which can be used pharmaceutically of the active compounds. Promote processing into preparations. Preparations prepared for oral administration can be in the form of tablets, dragees (also referred to as sugar-coated tablets, etc.), capsules, or solutions.

Drug preparations for oral use include combining the active compound with solid excipients, optionally grinding the resulting mixture (also referred to as grinding), and optionally obtaining tablets or dragee cores. It can be obtained by processing the mixture of granules, after adding the appropriate auxiliaries. Suitable excipients include, in particular, fillers such as sugars, such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potatoes. Starch, gelatin, tragacant rubber, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, a disintegrant may be added, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

The dragee core is properly coated. Concentrated sugar solutions may be used for this purpose, which optionally include arabic rubber, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solution. , And suitable organic solvents or solvent mixtures may be included. Dyes or dyes may be added to tablets or dragee coatings for identification purposes or to characterize different combinations of doses of active compounds.

Drug preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and plasticizers such as glycerol or sorbitol. Is included. Push-in capsules contain active ingredients such as fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate. It can be included in the mixture, and optionally with the stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol (PEGs). In addition, stabilizers may be added.
III. Definition

Specific terms are used here, but they are used only in a general and descriptive sense, and not for limiting purposes. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technology to which this currently described subject belongs.

The following terms relating to the compounds of formula (I) are believed to be well understood by those of ordinary skill in the art, but the following provisions are provided to facilitate the explanation of the subject matter of the present disclosure. .. These provisions are intended to supplement and exemplify, rather than exclude, provisions that would be apparent to those of ordinary skill in the art if the present disclosure is reviewed.

All substitutions, whether preceded by the term "optionally", and as used herein, are substituent and as recognized by those skilled in the art. It refers to the ability to convert one functional group into another, provided that the valence of the atom is maintained. When more than one position in any given structure can be replaced by more than one substitution component (substitutents) selected from a particular group, the substitution component is either the same or different at every position. It may be. Substitution components can also be further substituted (eg, aryl group substitution components may have another substituent off it, such as another aryl group, which may further be added. For example, it is replaced by fluorine at one or more positions).

When substituents or linking groups are specified by their customary chemical formula and written from left to right, they equally include chemically identical substituents that would result from writing the structure from right to left. And in the example, -CH ₂ O- is equivalent to -OCH _2- ; -C (= O) O- is equivalent to -OC (= O)-; -OC (= O) NR- is Equivalent to -NRC (= O) O- and other similar types.

When the term "chosen independently" is used, the substituted components referenced (eg, R groups, such as R ₁ , R ₂ , and other similar ones, or variables, eg , "M" and "n" etc.) can be the same or different. For example, both R ₁ and R ₂ can be substituted alkyl, or R ₁ can be hydrogen, and R ₂ can be substituted alkyl, and so on. ..

The terms "a", "an", or "a (n)", when used herein with respect to a group of substitutional components, mean at least one. For example, if a compound is substituted with an "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Furthermore, if the moyety (also referred to as the separated portion) is replaced by an R-substituted component, the group can be referred to as an "R-substituted". When a moisture is R-substituted, the moisture is substituted with at least one R-substituted component, and each R-substituted component is optionally different.

The nominated "R" or group will most likely have a structure recognized in the art as corresponding to a group having that name, unless otherwise specified here. For illustrative purposes, certain representative "R" groups described above are defined below.

The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group is substituted by one or more substitutional components, such substitutions conform to the principle of chemical bonding and are not inherently unstable and / or under ambient conditions, eg. , Aqueous, neutral, and some known physiological conditions, etc., are chosen to give compounds that may be unstable to those of ordinary skill in the art. For example, heterocycloalkyls or heteroaryls attach to the rest of the molecule via ring heteroatoms, depending on the principles of chemical bonding known to those skilled in the art, thereby resulting in essentially unstable compounds. Avoided.

The term hydrocarbon used herein refers to any chemical group, including hydrogen and carbon. Hydrocarbons can be substituted or unsubstituted. All valences must be met when any permutation is made, as will be known to those skilled in the art. Hydrocarbons can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Exemplary hydrocarbons are further defined herein below, and for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino. , And others of the same type.

The term "alkyl" is a linear (so-called unbranched) or branched, acyclic or cyclic hydrocarbon group, by itself or as part of another substitution component, unless otherwise stated. , Or a combination thereof, which can be fully saturated, mono- or poly-unsaturated, and can contain divalent and polyvalent groups and have a specified number of carbon atoms (so-called C). ₁ -C ₁₀ means one to ten carbons). In certain embodiments, the term "alkyl" is sufficient, including C _1-20 , linear (so-called "linear"), branched, or cyclic, saturated or at least partially and in some cases. Refers to unsaturated (so-called alkenyl and alkynyl) hydrocarbon radicals, which are derived from hydrocarbon moities containing between one and twenty carbon atoms by the removal of a single hydrogen atom.

Typical saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, Includes n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and their homologues and isomers.

"Branch" refers to an alkyl group to which a lower alkyl group, such as methyl, ethyl or propyl, adheres to a linear alkyl chain. A "lower alkyl" is an alkyl having 1 to about 8 carbon atoms (so-called C _1-8 alkyl), eg, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Mention the basis. A "higher alkyl" is an alkyl group having about 10 to about 20 carbon atoms, eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Mention. In certain embodiments, "alkyl" specifically refers to C _1-8 linear alkyl. In other embodiments, "alkyl" specifically refers to C _1-8 branched chain alkyl.

Alkyl groups can optionally be substituted with one or more alkyl group substituents (“substituted alkyl”), which can be the same or different. The term "alkyl group substituent" is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo. , And cycloalkyl. Optionally, one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms can be inserted along the alkyl chain, where the nitrogen-substituted component is hydrogen, lower alkyl (also also referred to herein as "alkylaminoalkyl"). , Or aryl.

As such, the term "substituted alkyl" as used herein includes an alkyl group, as defined herein, wherein one or more atoms or functional groups of the alkyl group are another atom or functional. The groups are substituted, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

The term "heteroalkyl" means a stable linear or branched chain, or cyclic hydrocarbon group, or a combination thereof, either by itself or in combination with another term, unless otherwise stated. Consists of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, where nitrogen, phosphorus, and sulfur atoms are optionally oxidized and to nitrogen. Terrorist atoms can be quaternized at will. Heteroatom (s), "(group)" used to indicate that there can be more than one) O, N, P and S, and Si are any internal positions of the heteroalkyl group, or Alkyl groups can be placed where they attach to the rest of the molecule. Examples are not limited to -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂₅ -S (O) -CH ₃ , -CH ₂ -CH ₂ -S (O) ₂ -CH ₃ , -CH = CH-O-CH ₃ , -Si (CH ₃ ) ₃ , -CH ₂ -CH = N-OCH ₃ , -CH = CH-N (CH ₃ ) -CH ₃ , O-CH ₃ , -O-CH ₂ -CH ₃ , and- Contains CN. Up to two or three heteroatoms may be contiguous, for example -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si (CH ₃ ) ₃ .

As mentioned above, the heteroalkyl groups used here include those groups that attach to the rest of the molecule through heteroatoms, such as -C (O) R', -C (O) NR', -NR'R. Includes things like'', -OR', -SR, and / or -SO ₂ R'. The terms heteroalkyl and -NR'R'' where "heteroalkyl" is defined, followed by an enumeration of certain heteroalkyl groups, such as -NR'R or others of its kind. It will be appreciated that are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are listed for added clarity. As such, the term "heteroalkyl" should not be construed here as excluding certain heteroalkyl groups, such as -NR'R'' or others of its kind.

"Cyclic" and "cycloalkyl" are non-aromatic monocyclics of about 3 to about 10 carbon atoms, eg 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Or refer to a polycyclic ring system. The cycloalkyl group can optionally be partially unsaturated. Cycloalkyl groups can also optionally be substituted with alkyl group substituents, oxo, and / or alkylene, as defined herein. Optionally, one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms can be inserted along the cyclic alkyl chain, where the nitrogen-substituted components are hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and Therefore, a heterocyclic group is provided. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphor, and noradamantyl, and fused ring systems such as dihydro and tetrahydronaphthalene, and others of the same kind. included.

The term "cycloalkylalkyl" as used herein refers herein to a cycloalkyl group as defined above, which also attaches to the parent molecule moisture through the alkyl group as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

The term "cycloheteroalkyl" or "heterocycloalkyl" is used as an unsaturated or partially unsaturated ring system, such as a 3- to 10-membered or unsubstituted cycloalkyl ring system. Mentioning that contains one or more heteroatoms, they can be the same or different, and nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si). ) Can be selected from the group and optionally contain one or more double bonds.

The cycloheteroalkyl ring can optionally be fused to or otherwise attached to another cycloheteroalkyl ring and / or a non-aromatic hydrocarbon ring. Heterocycles include those with one to three heteroatoms selected independently of oxygen, sulfur, and nitrogen, where nitrogen and sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms. Can be quaternized at will. In certain embodiments, the term heterocycle refers to a non-aromatic 5-, 6-, or 7-membered or polycyclic group, where at least one ring atom is from O, S, and N. Heteroatoms of choice (where nitrogen and sulfur heteroatoms may be optionally oxidized) and include, but are not limited to, bi- or tricyclic groups, one and one selected independently of oxygen, sulfur, and nitrogen. It contains a fused 6-membered ring with three heteroatoms, where (i) each 5-membered ring has 0 or 2 double bonds and each 6-membered ring has 0 or 2 double bonds. And each 7-membered ring has 0 to 3 double bonds, (ii) nitrogen and sulfur heteroatoms may be optionally oxidized, and (iii) nitrogen heteroatoms are optionally quaternary. And (iv) any of the above heterocycles may be fused to an aryl or heteroaryl ring. Typical cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazoridinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinucridinyl, morpholinyl, thiomorpholinyl, thiadiadinanyl, tetrahydrofuranyl, and others. Etc. are included.

The terms "cycloalkyl" and "heterocycloalkyl" represent cyclic versions of "alkyl" and "heteroalkyl", respectively, either by themselves or in combination with other terms, unless otherwise stated. Furthermore, for heterocycloalkyls, the heteroatom can occupy the position where the heterocycle attaches to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyls include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2. -Il, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and others of the same type are included. The terms "cycloalkylene" and "heterocycloalkylene" refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

Unsaturated alkyl groups are those that have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, Includes 1- and 3-propynyl, 3-butynyl, and even higher homologues and isomers. Alkyl groups restricted to hydrocarbon groups are referred to as "homoalkyl".

More specifically, the term "alkenyl" as used herein is linear or branched, including C _1-20 with at least one carbon-carbon double bond by removal of a single hydrogen atom. Mention monovalent groups derived from hydrocarbon moisture. Alkenyl groups include, for example, ethenyl (so-called vinyl), propenyl, butenyl, 1-methyl-2-butene-1-yl, pentanyl, hexenyl, octenyl, and butazienyl.

The term "cycloalkenyl" as used herein refers to cyclic hydrocarbons containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

The term "alkynyl" as used herein refers to a monovalent group derived from a linear or branched C _1-20 hydrocarbon of a design number of carbon atoms containing at least one carbon-carbon triple bond. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, heptinyl, and allenyl groups, and the like.

The term "alkylene" is 1 to about 20 carbon atoms, eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 depending on itself or part of another substitution component. , 11, 12, 13, 14, 15, 16, 17, 18, 19, or refers to linear or branched divalent aliphatic hydrocarbon groups derived from alkyl groups having 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group can also optionally be unsaturated and / or substituted with one or more "alkyl group substitution components". Optionally, one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also also referred to herein as "alkylaminoalkyl") can be inserted along the alkylene group, where the nitrogen-substituted components are described above. Alkyl. The exemplary alkylene groups include methylene (-CH _2- ); ethylene (-CH _2- CH _2- ); propylene (-(CH ₂ ) _3- ); cyclohexylene (-C ₆ H ₁₀ -);- CH = CH-CH = CH-;-CH = CH-CH ₂ -;-CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CH = CHCH _2- , -CH ₂ CsCCH _2- , -CH ₂ CH ₂ CH (CH ₂ CH ₂ CH ₃ ) CH ₂ -,-(CH ₂ ) _q -N (R)-(CH ₂ ) _r -is included, and in the equation, each q and r is 0 to about 20 independently. Up to, examples are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, And R are hydrogen or lower alkyl; methylenedioxyl (-O-CH ₂ -O-); and ethylenedioxyl (-O- (CH ₂ ) ₂ -O-). The alkylene group can have about 2 to about 3 carbon atoms, and can have an additional 6-20 carbon atoms. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, and those groups have 10 or less carbon atoms in some embodiments of the present disclosure. A "lower alkyl" or "lower alkylene" is an alkyl or alkylene group with a shorter chain and usually has up to eight carbon atoms.

The term "heteroalkylene" means, but is not limited to, a divalent group derived from heteroalkyl, either by itself or as part of another substitution component, but without limitation -CH ₂ -CH ₂ -S-CH _2- CH ₂ - and _{-CH 2 -S-CH 2 -CH 2} -NH-CH 2 - it is exemplified by. For heteroalkylene groups, the heteroatom can also occupy either or both of the chain ends (eg, alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and others of the same kind). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula for the linking group is written does not imply the direction of the linking group. For example, the formula -C (O) OR'-represents both -C (O) OR'- and -R'OC (O)-.

The term "aryl" can be a monocyclic or multi-ring (eg, 1 to 3 rings, etc.) linked together by condensation or covalent bond, unless otherwise stated, aromatic hydrocarbons. Means a substitution component. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms selected from N, O, and S (in each separate ring in the case of multiple rings). , Where nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule through carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolill, 3-pyrrolill, 3-pyrazolyl, 2-imidazolyl, 4- Imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- Frill, 3-frill, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, prynyl, 2-benzimidazolyl, 5-indyl, 1 -Includes isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Each substituent of the aryl and heteroaryl ring system described above is selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

For brevity, the term "aryl" includes both aryl and heteroaryl rings as defined above when used in combination with other terms (eg, aryloxo, aryltioxo, arylalkyl). Is done. Therefore, the terms "arylalkyl" and "heteroarylalkyl" are those groups to which aryl or heteroaryl groups attach to alkyl groups (eg, benzyl, phenethyl, pyridylmethyl, frillmethyl, and the like). Those alkyl groups (eg, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy)) in which carbon atoms (eg, methylene groups) are replaced, for example, by oxygen atoms. Means to be included, including propyl, and others of the same type. However, the term "haloaryl" as used herein means to cover only aryls that are replaced by one or more halogens.

When a heteroalkyl, heterocycloalkyl, or heteroaryl contains a specific number of members (eg, "3-7 members"), the term "member" refers to a carbon or heteroatom.

In addition, generally the formula:
The structures represented by are, as used herein, ring structures, such as, but are not limited to, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, and others of the same kind. , Aliphatic and / or aromatic cyclic compounds, including saturated ring structures, partially saturated ring structures, and unsaturated ring structures, containing a substituent R group, in which the R group is present or absent. Possible, and when present, one or more R groups can each be substituted with one or more available carbon atoms of the ring structure. The presence or absence of R groups and the number of R groups is determined by the value of the variable "n", which is usually an integer with values ranging from 0 to the number of carbon atoms in the ring available for substitution. Each R group is replaced with an available carbon of the ring structure rather than by another R group if there is more than one. For example, the above structure, where n is 0 to 2, does not limit the group of compounds, but:
And other similar types are included.

A dashed line representing a bond in a cyclic ring structure indicates that the bond can be present or absent in the ring. That is, the dashed line representing the bond in the cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

Indicates the point of attachment of the moisture to the rest of the molecule.

When a designated atom of an aromatic ring or a heterocyclic aromatic ring is defined as "absent", the designated atom is replaced by a direct bond.

Each of the above terms (eg, "alkyl", "heteroalkyl", "cycloalkyl, and" heterocycloalkyl "," aryl "," heteroaryl "," phosphonate ", and" sulfonate "and two of them. Valuable derivative) means to include both substituted and unsubstituted forms of the indicated groups. Optional substitution components for each type of group are provided below.

Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivative groups (referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl. Substitution components for (including groups with many) are not limited, but the following: -OR', = O, = NR', = N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC (O) R', -C (O) R', -CO ₂ R', -C (O) NR'R'', -OC (O) NR 'R'', -NR''C (O) R', -NR'-C (O) NR''R''', -NR''C (O) OR', -NR-C (NR'R'') = NR''', -S (O) R', -S (O) ₂ R', -S (O) ₂ NR'R'', -NRSO ₂ R', -CN and -NO _{Of 2} , it can be one or more of the various groups chosen in numbers ranging from zero to (2m' + 1), where m'is the total number of carbon atoms in such groups. .. R', R'', R'''and R'''' are independent of hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted. Aryl (eg, aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups can be referred to. As used here, the "alkoxy" group is an alkyl that attaches to the rest of the molecule through divalent oxygen. When the compounds of the present disclosure contain more than one R group, for example, each R group will have these groups as well as the respective R', R'', R'''and R'''' groups. Are chosen independently when there are more than one. When R'and R'' attach to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' means to include 1-pyrrolidinyl and 4-morpholinyl, but not limited. From the above discussion of substituents, experts in the art have found that the term "alkyl" is a group containing a carbon atom attached to a group other than a hydrogen group, eg, haloalkyl (eg, -CF ₃ and -CH _2). CF ₃ ) and acyls (eg, -C (O) CH ₃ , -C (O) CF ₃ , -C (O) CH ₂ OCH ₃ , and others of the same kind) and so on. You will understand that it means that.

As with the substituents described for alkyl groups above, exemplary substituents for aryl and heteroaryl groups (and their divalent derivatives) vary, and for example: halogen, -OR' , -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC (O) R', -C (O) R', -CO ₂ R', -C (O) NR'R'', -OC (O) NR'R'', -NR''C (O) R', -NR'-C (O) NR''R''', -NR''C (O) OR', -NR-C (NR'R''R''') = NR'''', -NR-C (NR'R'') = NR'''-S (O) ) R', -S (O) ₂ R', -S (O) ₂ NR'R'', -NRSO ₂ R', -CN and -NO ₂ , -R', -N ₃ , -CH (Ph) ) ₂ , Fluoro (C ₁ -C ₄ ) Alkoxo, and Fluoro (C ₁ -C ₄ ) Alkyl, in numbers ranging from zero to the total number of open valences in the aromatic ring system. Selected; and there, R', R'', R'''and R'''' are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or non-substituted. It can be selected independently from substituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compounds of the present disclosure contain more than one R group, for example, each R group will have these groups as well as the respective R', R'', R'''and R'''' groups. When more than one is present, it is chosen independently.

The two substitution components at the adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of formula -TC (O)-(CRR') _q -U-, where T and U are independent. , -NR-, -O-, -CRR'-or single bond, and q is an integer from 0 to 3. Alternatively, the two substituents on the flanking atoms of the aryl or heteroaryl ring may optionally be substituted by the substituents of the formula -A- (CH ₂ ) _r -B-, where A and B are irrelevant. To -CRR'-, -O-, -NR-, -S-, -S (O)-, -S (O) _2- , -S (O) ₂ NR'-or single bond, and r Is an integer from 1 to 4.

One of the single bonds of the new ring so formed can optionally be replaced by a double bond. Alternatively, the two substitution components at the adjacent atoms of the aryl or heteroaryl ring may optionally be substituted by the substitution components of the formula (CRR') _s -X'-(C''R''') _d-. , So s and d are integers from 0 to 3 regardless, and X'is -O-, -NR'-, -S-, -S (O)-, -S (O) _2- , or -S (O) ₂ NR'-. Substitution components R, R', R'' and R''' are independent of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substitutions. Alternatively, it can be selected from unsubstituted heteroaryl.

As used herein, the term "acyl" refers to an organic acid group in which the carboxyl group -OH is replaced by another substituent and has the general formula RC (= O)-, where R is here. (Alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or aromatic heterocyclic group as specified in). As such, the term "acyl" specifically includes those such as arylacyl groups such as acetylfuran and phenacyl groups. Specific examples of acyl groups include acetyl and benzoyl.

The terms "alkoxy" or "alkoxy" are used interchangeably herein and are saturated (so-called alkyl-O-) or unsaturated (so-called alkenyl-O- and alkynyl-) attached to the parent molecule moyety through oxygen atoms. Refers to the O-) group, where the terms "alkyl,""alkoxy," and "alkynyl" are as described above, and include C _1-20 , linear, branched, or cyclic, saturated or Unsaturated oxo hydrocarbon chains can be included, for example, methoxyl, alkoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, t-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, And others of the same type are included.

The term "alkoxyalkyl" as used herein refers to alkyl-O-alkyl ethers such as methoxyethyl or ethoxymethyl groups.

"Aryloxyl" refers to an aryl-O-group whose aryl group is as described above and includes substituted aryls. The term "aryloxyl" as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.

"Aralkyl" refers to an aryl-alkyl-group, where aryl and alkyl are as described above, and include substituted aryl and substituted alkyl. Typical aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

"Aralkyloxygen" refers to the Aralkyl-O-group, where the Aralkyl group is as described above. The exemplary aralkyloxyl group is benzyloxyl.

"Alkoxycarbonyl" refers to an alkyl-O-CO- group. Typical alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.

"Aryloxycarbonyl" refers to the aryl-O-CO-group. Typical aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

"Aralkoxycarbonyl" refers to the Aralkoxycarbonyl group. The exemplary aralkylcarbonyl group is benzyloxycarbonyl.

"Carbamoyl" refers to the amide group of formula-CONH ₂ . "Alkylcarbamoyl" refers to the R'RN-CO- group, where one of R and R'is hydrogen, and the other of R and R'is alkyl and / or substituted alkyl as described above. .. "Dialkylcarbamoyl" refers to the R'RN-CO- group, where each R and R'is an alkyl and / or substituted alkyl as described above, regardless.

The term carbonyldioxyl used herein refers to the carbonate group of formula-O-CO-OR.

"Acyloxyl" refers to the acyl-O-group in which the acyl is as described above.

The term "amino" refers to _two -NH groups, and also to nitrogen-containing groups known in the art derived from ammonia by replacing one or more hydrogen radicals with organic radicals. For example, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic radicals that have acyl and alkyl substituents, respectively.

As used herein, "aminoalkyl" refers to an amino group covalently attached to an alkylene linker. More specifically, the terms alkylamino, dialkylamino, and trialkylamino used herein attach to the parent molecule Moety through a nitrogen atom and are one, two, or three alkyl, respectively, as defined above. Mention the basis. The term alkylamino refers to a group having structure-NHR'where R'is the previously defined alkyl group; while the term dialkylamino refers to a group having structure-NR'R''. However, R'and R'' are independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R''R''', where R', R'', and R''' are independently selected from the group consisting of alkyl groups. .. In addition, R', R'', and / or R''' can be optionally-(CH ₂ ) _k- , where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.

The amino group is -NR'R'', where R'and R'' are typically hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted. It is selected from substituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The terms alkyl thioethers and thioalkoxys refer to saturated (so-called alkyl-S-) or unsaturated (so-called alkenyl-S- and alkynyl-S-) groups attached to the parent molecule moyer through the sulfur atom. Examples of thioalkoxyl moisties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and others of the same type.

"Acylamino" refers to the acyl-NH- group, where the acyl is as described above. "Aloylamino" refers to the aloyl-NH- group, where aloyl is as described above.

The term "carbonyl" refers to the-(C = O) -group.

The term "carboxyl" refers to the -COOH group. Such groups are also referred to herein as "carboxylic acid" moities.

The terms "halo", "halide", or "halogen" as used herein refer to fluoro, chloro, bromo, and iodo groups. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C _1- C ₄ ) alkyl" is not limited, but is limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Means to include.

The term "hydroxyl" refers to the -OH group.

The term "hydroxyalkyl" refers to alkyl groups substituted with -OH groups.

The term "mercapto" refers to the -SH group.

The term "oxo" as used herein means an oxygen atom that is double bonded to a carbon atom or another element.

The term "nitro" refers to _two -NOs.

The term "thio" refers herein to the compounds mentioned above, where carbon or oxygen atoms are replaced by sulfur atoms.

The term "sulfate" refers to _four SOs.

The term thiohydroxyl or thiol used herein refers to -SH.

The term ureido refers to the urea group of formula-NH-CO-NH ₂ .

Unless explicitly specified otherwise, the "substituents" used herein include functional groups selected from one or more of the following moities as defined herein:
(A) -OH, -NH ₂ , -SH, -CN, -CF ₃ , -NO ₂ , oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted Aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituted with at least one of the following substituents:
(I) Oxo, -OH, -NH ₂ , -SH, -CN, -CF ₃ , -NO ₂ , halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted Aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl (a) oxo, -OH, substituted with at least one substituent selected from: -NH ₂ , -SH, -CN, -CF ₃ , -NO ₂ , halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) Oxo, -OH, -NH ₂ , -SH, -CN, -CF ₃ , -NO ₂ , halogen, unsubstituted alkyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclo Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl substituted with at least one substituent selected from alkyl, unsubstituted aryl, and unsubstituted heteroaryl.

As used herein, "lower reproduced" or "lower substituents" means a group selected from all of the above-mentioned substituents for a "substituent", where each substituted or non-substituted group. Substituent alkyl is a substituted or unsubstituted C _1- C ₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted cycloalkyl. It is a C _5- C ₇ cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

As used herein, "size-restricted substituent" or "size-restricted substituent" means a group selected from all the above-mentioned substituents for "substituent", where each substituted or unsubstituted alkyl is substituted or non-substituted. Substituted C _1- C ₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C _4- C ₈ cycloalkyl And each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

Throughout the specification and claims, the chemical formula or name given should include all tautomers, homologues, and optical-and stereoisomers, as well as racemic mixtures in which such isomers and mixtures are present. Is.

Certain compounds of the present disclosure have an asymmetric carbon atom (optical or chiral center) or double bond; with respect to enantiomers, racemic compounds, diastereomers, metamutants, geometric isomers, absolute stereochemistry ( Stereoisomeric forms that can be defined as R)-or (S)-or as (D)-or (L)-for an amino acid, and individual isomers are included within the scope of this disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable for synthesis and / or separation. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)-and (S)-or (D)-and (L) -isomers are prepared using chiral synthons or chiral reagents, or degraded using conventional techniques. obtain. When a compound described herein contains an olefin bond or other center of geometric asymmetry, and unless otherwise stated, the compound is intended to contain both E and Z geometric isomers.

Unless stated otherwise, the structures depicted herein also mean that all stereochemical forms of the structure; so-called, for each asymmetric center, include the configuration of R and S. Therefore, a single stereochemical isomer of the compound and a mixture of enantiomers and diastereomers are within the scope of the present disclosure.

It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of this disclosure. The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer to another.

Unless otherwise stated, the structures depicted herein also mean that they contain compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure except for hydrogen substitution by deuterium or tritium, or carbon substitution by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

The compounds of the present disclosure may also contain an unnatural proportion of atomic isotopes in one or more atoms that make up such a compound. For example, the compound may be radioactively labeled with a radioisotope, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of this disclosure are included within the scope of this disclosure, whether radioactive or not.

As used herein, the term "monomer" refers to a molecule that is capable of undergoing polymerization, thereby giving the polymer or a building block to the essential structure of the polymer.

A "polymer" is a molecule with a high relative molecular mass, the structure of which essentially comprises multiple repetitions of low relative molecular weight, a unit derived from the molecule of the monomer.

The "oligomer" used herein includes, for example, a small number of monomer units, as opposed to polymers that can contain a potentially unlimited number of monomers. Dimers, trimers, and tetramers are non-limiting examples of oligomers.

The compounds of the present disclosure can exist as salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (eg, tartrate). Includes salts with (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures, oxalates, benzoates and amino acids, such as glutamates, etc. These salts Can be prepared by methods known to those skilled in the art, and also includes such as base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, the acid addition salt should be in a sufficient amount, either in a neat or suitable inert solvent, in the neutral form of such a compound. It can be obtained by contact with the desired acid. Examples of acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitrate, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogencarbonic acid ( Derived from inorganic acids such as monohydrogenphosphoric acid), dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphite and the like, as well as Acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methane Includes salts derived from organic acids such as sulfonic acids, and others of the same kind, as well as salts of amino acids, such as alginates and other of the same kind, and glucuronic acid or galacturone. Also included are salts of acids and other organic acids such as those of the same kind. Certain compounds of the present disclosure are basic and acidic that allow the compound to be converted to either a base addition salt or an acid addition salt. Contains both functional groups of.

The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in customary manners. The parental form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents.

Certain compounds of the present disclosure can be present in both solvated and solvated forms, including hydrated forms. In most cases, the solvated form is equivalent to the non-solvated form and is included within the scope of the present disclosure. Certain compounds of the present disclosure may be present in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the intended use by this disclosure and are intended to be within the scope of this disclosure.

The term "pharmaceutically acceptable salt" includes salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substitution component moisture found in the compounds described herein. Means that. When the compounds of the present disclosure contain relatively acidic functional groups, by contacting the neutral form of such compounds with a sufficient amount of the desired base, either in neat or in a suitable inert solvent. A base addition salt can be obtained. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amino, or magnesium, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either in neat or in a suitable inert solvent. An acid addition salt can be obtained. Examples of pharmaceutically acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, carbonic acid monohydrogen, phosphoric acid, phosphoric acid monohydrogen, phosphoric acid dihydrogen, sulfuric acid, sulfuric acid monohydrogen, iodide. Derived from inorganic acids such as hydrides, phobic acids and the like, as well as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, Contains salts derived from relatively non-toxic organic acids such as lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and others of the same kind. Is done. It also includes salts of amino acids, such as those such as alginate, and salts of organic acids such as glucuronic acid or galacturic acid and others of the same kind {eg, Berge et al., "Pharmaceutical". See Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19}. Certain specific compounds of the present disclosure include both basic and acidic functional groups that allow the compound to be converted to either a base addition salt or an acid addition salt.

In addition to the salt form, the present disclosure provides compounds in the prodrug form. The prodrugs of the compounds described herein are those compounds that are effortlessly subject to chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in the Exvivo environment. For example, a prodrug can be slowly converted to a compound of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

The term "protecting group" is used to block some or all reactive motives of a compound and prevent such motives from engaging in a chemical reaction until the protecting group is removed, such as TW. Listed in Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. (3rd Edition) John Wiley & Sons (1999), And mention those chemistry described. If different protecting groups are employed, it may be advantageous for each (different) protecting group to be removable by different means. Protecting groups that are cleaved under distinct reaction conditions as a whole allow different removal of such protecting groups. For example, protecting groups can be removed by acid, base, and hydrocracking. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid-labile and Cbz groups that can be removed by hydrocracking, and Fmoc groups that are base-labile. Can be used to protect carboxy and hydroxyreactive moities in the presence of amino groups protected by. Carboxylic acids and hydroxyreactive moities are blocked by acid-labile groups, such as those such as tert-butylcarbamate, or by hydrolyzable and removable carbamates that are stable to both acids and bases. In the presence of the amine, it can be blocked by base-labile groups, such as methyl, ethyl, and acetyl, without limitation.

Carboxylic acids and hydroxyreactive moities may also be blocked by hydrolytically removable protecting groups, such as benzyl groups, while amine groups capable of hydrogen bonding to the acid. , Can be blocked by base instability groups, such as Fmoc. Carboxylic acid-reactive moities may be blocked by oxidatively removable protecting groups, such as 2,4-dimethoxybenzyl, while coexisting amino groups are fluoride-labile. Can be blocked by silylcarbamate.

Allyl blocking groups (also referred to as allyl protecting groups) are useful in the presence of acid- and base-protecting groups, because the former is stable and can be subsequently removed by a metal or pyric acid catalyst. .. For example, an allyl-blocked carboxylic acid can be deprotected by a palladium (O) -catalyzed reaction in the presence of acid-labile t-butyl carbamic acid or base-labile amine acetate protecting group. .. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue adheres to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional groups are reactive.

Typical blocking / protecting groups include, but are not limited to, the following motives:

The subjects treated in many of those embodiments by the methods of the present disclosure are preferably human subjects, but the methods described herein are valid for all vertebrate species and are included in the term "subject". It is understood that it is intended to be. Thus, a "subject" is a human subject for medical purposes, such as treatment of an existing condition or disease or prophylactic treatment to prevent the development of a condition or disease, or for medical or veterinary purposes. Alternatively, it can include animal objects for development purposes. Suitable animal subjects include mammals, but not limited to primates, such as humans, monkeys, apes, and others of the same species; bovids of the genus or close to it, eg. Cows (cattle), bulls (oxen), and other similar species; sheep-like (ovines), eg sheep (sheep) and other similar species; goat-like (caprines) ), Examples include goats (goats) and other similar species; mammals (porcines), examples include pigs (pigs), edible pigs (hogs), and other similar species; horses Such as (equines), eg horses, donkeys, zebras, and others of the same kind; including felines, wild and domestic cats (cats); like dogs. Including canines, dogs; including lagomorphs, rabbits, norabbits (hair), and other similar species; and rodents, mice Included, including those including, rats, and others of the same type. The animal can be a transgenic animal. In some embodiments, the subject is a human, but not limited to, a fetus, a newborn, an infant, a juvenile, and an adult subject. In addition, "subjects" can include patients who suffer or are suspected of suffering from a condition or illness. Therefore, the terms "object" and "patient" are used interchangeably here.

In general, the "effective amount" of an active drug or drug delivery device refers to the amount required to elicit the desired biological response. Effective amounts of drug or device are the desired biological endpoint, the drug to be delivered, the composition of the encapsulation matrix, the target tissue, and others, as will be appreciated by those of ordinary skill in the art. It can vary depending on factors such as the type.

In accordance with long-standing patent law practice, the terms "a", "an", and "the" are used in this application, including the claims, as "one or more". Many (also called more than one) ”. Thus, unless, for example, the context is clearly opposite (eg, multiple subjects), and so on, a reference to "a subject" includes multiple subjects.

Throughout this item and claims, "comprise (including, having as a component, etc.)", "comprises (including, having as a component, etc.)", and "comprising (including, having as a component, etc.)", etc. ) ”Is used in a non-exclusive sense, unless the context requires otherwise. Similarly, the term "include" and its grammatical variants allow the enumeration of items in a list to replace or add to the listed items. Intended to be non-restrictive so as not to exclude other similar items.

For the purposes of this item and the scope of the accompanying claims, quantities, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, properties, and unless otherwise indicated. All numbers representing other numbers used in this specification and in the scope of claims are referred to as "about" in all cases, even if the term "about" may not explicitly appear with the value, quantity or range. It should be understood that it is modified by the term. Therefore, unless otherwise indicated, the numerical parameters represented in the following items and claims are not exact and need not be exact, but tolerances, conversion factors, rounding, measurement errors and others. Approximate and / or larger as necessary, reflecting other factors known to those skilled in the art, such as those of the same type, and the desired properties required to be obtained by the subject matter currently disclosed. Or it may be smaller. For example, when referring to a value, the term "about" refers to ± 100% in some embodiments, ± 50% in some embodiments, ± 20% in some embodiments, and some from the specified amount. Includes variations that are ± 10% in embodiments, ± 5% in some embodiments, ± 1% in some embodiments, ± 0.5% in some embodiments, and ± 0.1% in some embodiments. It can mean that such variations are appropriate to carry out the disclosed methods or to adopt the disclosed compositions.

In addition, the term "about", when used in connection with one or more numbers or numerical ranges, refers to all such numbers, including all numbers in the range, and above and below the numbers represented. It should be understood that the range is modified by extending the boundaries of. For enumeration of numeric ranges by endpoints, all numbers contained within that range, for example, whole integers, their fractions (eg, for enumeration of 1-5, 1, 2, 3, 4, and 5). , As well as their fractions, examples include 1.5, 2.25, 3.75, 4.1, and others of the same kind), and any range within that range.

The following examples have been included to provide guidance to those of ordinary skill in the art for the practice of typical embodiments of the subject matter of the present disclosure. In light of the general level of proficiency in the present disclosure and the present art, the profession intends the following examples to be exemplary only, and a vast number of modifications, modifications, and alternatives are within the scope of the subject matter of this disclosure. It can be admitted that it can be adopted without leaving. The following synthetic descriptions and specific examples are intended for illustrative purposes only and should not be construed as limiting in any way to produce the compounds of the present disclosure by other means. Absent.

Example 1

Method

Comparative tissue distribution of 2-PMPA prodrug equal moles of 2-PMPA in nude mice or NSG mice carrying C4-2 prostate cancer tumors.

Nude mice were given either 2-PMPA or the prodrug LTP-144 or Tris-POC-2-PMPA (Compound 10 in Table 1) prior to brief isoflurane anesthesia and salt solution perfusion. (5 mg / kg or molar equivalent, ip (intraperitoneal)), and sacrificed after 30 minutes. The kidneys were removed and flash frozen in liquid nitrogen. Using the LC / MS-MS based bioanalysis described above (Majer et al., 2016), each tissue sample was evaluated for 2-PMPA concentration. In addition, a prodrug of the urea-based PSMA ligand ZJ-43, which has a promoyity modification similar to Tris-POC-2-PMPA, was tested using a similar method.

To generate a C4-2 in vivo model, 3 × 10 ⁶ LNCaP-C4-2 cells were subcutaneously injected into the flank of male NSG mice. When the tumor grew to approximately 600-800 mm ³ , the tumor was resected, aseptically cut into 2-mm x 2-mm pieces, and frozen back viably (5% DMSO / 95). % FBS). Tumors did not pass from mouse to mouse more than 4 times. For this experiment, two vials of viable frozen explants were thawed at 37 ° C. Extratumor debris was washed in RPMI without FCS and then surgically transplanted into the subcutaneous pocket in male NSG mice. When the tumor reached 600-800 mm ³ , the mice were euthanized, the tumor was aseptically resected, and cut into 2-mm x 2-mm pieces before re-implantation in 40 mice. Pharmacokinetic experiments were performed when the tumor reached 500-700 mm ³ . 2-PMPA (3 mg / kg, iv) or molar equivalent of Tris-POC-2-PMPA (7.62 mg / kg, iv), vehicle (5% EtOH / 10% Tween 80/85% 50 mM HEPES) After dissolution, injection was performed via the tail vein. Mice were then euthanized under isoflurane anesthesia after 0.25, 0.5, 1, 3, or 6 hours (n = 3 / group). Blood was collected in EDTA-lined tubes by cardiac puncture and stored on ice until the ginger was separated by centrifugation. Salivary glands, kidneys, and tumors were harvested and snap frozen on dry ice. All tissues were stored at -80 ° C prior to bioanalysis.

Displacement study in non-tumor-bearing NMRI mice

⁶⁸ Ga-PSMA-617 was synthesized as previously described (Afshar-Oromieh et al., 2015). The specific activity of the radiopharmaceutical used in the presented animal studies (20 MBq ⁶⁸ Ga tagged with 0.2-0.8 μg precursor peptide) corresponds to that used in clinical applications (Afshar-Oromieh et al., Et al. 2015). Three tumor-free NMRI mice were injected with 20 MBq of ⁶⁸ Ga-PSMA-617 via the tail vein. One hour after injection, mice were imaged with a dedicated small animal PET scanner (Siemens, Inveon) for sufficient time to bind a particular tracer to renal PSMA and remove the unbound tracer from the calyx. And quantified renal uptake (baseline scan). Immediately after the baseline scan, 16 μg of Tris-POC-2-PMPA (0.5 mg / kg * 32.1 g body weight (BW) of all mice) in 100 μL of salt solution was injected via the tail vein. After another hour, so-called PET tracer injections, 2 hours later, ⁶⁸ Ga-PSMA-617 renal uptake was reassessed per animal PET (replacement scan).

Replacement study in nude mice carrying LNCaP tumor xenografts

5 * 10 ⁶ LNCaP cells (BD Biosciences) were transplanted behind the left shoulder of n = 3 nude mice; tumors were approximately 1-cm in diameter 8-12 weeks after inoculation. Reached. Baseline uptake of radiopharmaceuticals in kidneys and tumors was performed by animal PET scans (Siemens, Inveon) 1 hour after injection of ⁶⁸ Ga-PSMA-617 (10-40 MBq ⁶⁸ Ga tagged with 0.4 μg PSMA-617 precursor). ) Quantified. Immediately after the baseline scan, animals were injected with 0.5 mg / kg BW or 0.05 mg / kg BW Tris-POC-2-PMPA in 100 μg salt solution or pure salt solution as a control. After an additional hour, so-called PET tracer injections, 2 hours later, uptake of ⁶⁸ Ga-PSMA-617 in kidneys and tumors was reassessed per second animal PET (replacement scan).

Kidney and salivary gland uptake in healthy human subjects examined with ⁶⁸ Ga-PSMA-617 with and without pre-dosing of Tris-POC-2-PMPA

From a pair of patients (Siemens, mCT) imaged 0.1 hours, 1 hour, 2 hours, 3 hours and 4 hours prior to injection of ⁶⁸ Ga-PSMA-617 (Afshar-Oromieh et al., 2015), the associated tumor load ( One subject without <5 mL) was selected to quantify the uptake of physiological spontaneous tracers in the kidneys and salivary glands during the examination. For an intervention experiment, 15 minutes prior to applying the PET tracer, 5 mg (0.05 mg / kg BW) of Tris-POC-2-PMPA solution (in 2.5 mL of 30% ethanol) was given to one healthy volunteer. I injected it. Again, perform PET scans (Siemens, mCT) 0.1 hours, 1 hour, 2 hours, 3 hours and 4 hours after injection of ⁶⁸ Ga-PSMA-617, and for tracer uptake over time in the kidneys and salivary glands. Quantified for each SUVmax (maximum standardized capture value).

Incorporation of tumors, kidneys and salivary glands in prostate cancer patients examined with ⁶⁸ Ga-PSMA-617 with and without pre-medication of Tris-POC-2-PMPA

One patient was PET imaged 1 hour after injection of 68Ga-PSMA-617 and quantified by SUVmax for tracer uptake in tumors, kidneys and salivary glands. Later, the same patient was imaged using the same protocol, but with a 10 mg (0.1 mg / kg BW) Tris-POC-2-PMPA solution (in 2.5 mL of 30% ethanol) 15 minutes before application of the PET-tracer. Preprocessed.

Incorporation of tumors, kidneys and salivary glands in prostate cancer patients treated and imaged with ¹⁷⁷ Lu-PSMA-617 with and without Tris-POC-2-PMPA premedication

¹⁷⁷ Lu-PSMA-617 follows the updated Helsinki Declaration, Paragraph 37, “Unproven Interventions in Clinical Practice”, and priorities for all approved treatments (without contraindications). Surrogate in accordance with German regulations for "compassionate use," including confirmation of the indication by both nuclear medicine physicians and external experts in urology or oncology. Provided as therapy). No systematic patient selection was performed, except that all patients had to present a PSMA-positive tumor phenotype based on PSMA imaging. All patients were informed about the experimental nature of this therapy and were given written informed consent. The institutional review committee approved this retrospective study. The two patients were pretreated with Tris-POC-2-PMPA prior to administration of ¹⁷⁷ Lu-PSMA-617. Gamma-ray imaging was then performed over several hours, and estimates of exposure dosimetry were calculated for healthy organs and metastatic lesions and compared to historical controls that were not pretreated with Tris-POC-2-PMPA. .. The dosimetric data presented here from historical controls are derived from patients treated at our center under the same protocol as previously reported (J Nucl Med. (Journal of Nuclear Medicine)). August 2016; 57 (8): 1170-6.). All dosimetry methods were performed as previously described in the report (J Nucl Med., 2016 Aug; 57 (8): 1170-6).

Example 2

result

Initially, the prodrug Tris-POC-2-PMPA was shown to deliver high levels of 2-PMPA to the kidney in pharmacokinetic / tissue distribution studies in mice. Second, in mice carrying prostate cancer tumors, Tris-POC-2-PMPA was 3- and 57-fold 2-fold to rodent salivary glands and kidneys, respectively, relative to prostate cancer xenografts. Priority delivery of PMPA was shown. Tris-POC-2-PMPA has been shown to significantly reduce renal uptake of PET tracer ⁶⁸ Ga-PSMA-617 targeting PSMA in normal mice. When tested in prostate cancer tumor-bearing mice, Tris-POC-2-PMPA selectively reduced renal uptake of ⁶⁸ Ga-PSMA-617, but tumor uptake was well preserved. In a pilot experiment with healthy human males, pretreatment with Tris-POC-2-PMPA was performed as in mice. Pre-administration of Tris-POC-2-PMPA replaced the subsequent binding of ⁶⁸ Ga-PSMA-617 to the kidney and salivary glands by approximately 65%. By intra-individual comparison with prostate cancer patients, pre-administration of Tris-POC-2-PMPA resulted in ⁶⁸ Ga-PSMA-617 binding to the kidney, only over 75%, and 35 salivary gland binding. Only more than% was replaced, but tracer tumor uptake was well avoided. Tris-POC-2-PMPA was given to two prostate cancer patients later before injecting ¹⁷⁷ Lu-PSMA-617 for radiation therapy. Tris-POC-2-PMPA shields both salivary glands (72% dose reduction) and kidney (45% dose reduction) and is significant at radiation therapy exposure in prostate cancer tumors compared to historical controls No significant effect. Together, these data show that while Tris-POC-2-PMPA or similar prodrugs were able to selectively protect healthy organs (eg, kidneys, lacrimal glands, and salivary glands) from radioligand binding. , Suggest that it does not interfere with tumor uptake of radioligands during PSMA-targeted imaging or radiotherapy.

Comparative tissue distribution of 2-PMPA prodrug equal moles of 2-PMPA in nude mice

Compared to equimolar doses of 2-PMPA, LTP144 and Tris-POC-2-PMPA resulted in significantly increased concentrations of 2-PMPA in the kidney. Tris-POC-2-PMPA showed the most favorable distribution, with increased delivery of 2-PMPA to the kidney by more than 20 (Figure 1). In contrast to the 2-PMPA prodrug disclosed here, a similar prodrug of the alternative urea-based PSMA ligand, ZJ-43, with respect to parental administration of ZJ-43 (Fig. 2A) mouse kidney or salivary gland. No increased distribution to (Fig. 2B).

Tris-POC-2-PMPA (Compound 10 in Table 1) preferentially delivers 2-PMPA to mouse salivary glands and kidneys compared to prostate cancer xenografts.

Concentrations of 2-PMPA in hemorrhage, tumors, salivary glands, and kidneys of either 2-PMPA or Tris-POC-2-PMPA (3 mg / kg or molar equivalent, iv), human C4-2 prostate cancer cells Measured at multiple time points after tail vein administration to NSG mice with subcutaneous heterologous implants (FIGS. 3A and 3B). TRIS-POC-2-PMPA administration resulted in 17.5 h * nmol / g and 374 h * nmol / g of exposure to 2-PMPA salivary glands and kidneys, 3 and 57 times more than those observed in tumors. (Fig. 3B). When 2-PMPA was administered directly (Fig. 3A), salivary gland and kidney exposure was 1.76 h * nmol / g and 94.8 h * nmol / g, 10 and more than those reached by TRIS-POC-2-PMPA delivery. It was four times lower. Therefore, TRIS-POC-2-PMPA provided a significant improvement in saliva: tumor and kidney: tumor 2-PMPA concentration ratios.

Replacement study in non-tumor-bearing NMRI mice

Mean renal uptake at baseline scan was 3.4 mSUV (Figure 4A). In a replacement scan (Figure 4B), radioactivity was almost entirely replaced from the kidney by residual uptake of 0.3 mSUV (<10% baseline uptake).

Replacement study in nude mice with LNCaP tumor xenografts

At baseline scan, mean tumor uptake was mSUV1.02 and mean renal uptake was mSUV2.36 (Figure 5A). In the replacement scan (Figure 5B), tumor uptake remained largely unchanged, with an average mSUV of 1.00 for the two premedicated animals, which received only salt solution to stimulate diuresis. It was just a little higher than the animals (mSUV 0.84). Renal uptake after Tris-POC-2-PMPA injection was replaced by mSUV0.24, which was achieved 50% lower than in so-called forced diuresis (control: mSUV0.47).

Incorporation of kidneys and salivary glands in healthy human subjects examined with ⁶⁸ Ga-PSMA-617 with and without pre-medication of Tris-POC-2-PMPA

Biological distribution of physiological ⁶⁸ Ga-PSMA-617 in a control patient without pre-medication of Tris-POC-2-PMPA (Fig. 6A, left; maximum projection 1 h pi), and kidney (Fig. 6C) and parotid gland. Its typical pharmacokinetics in (Fig. 6D) are in good agreement with previous publications (Afshar-Oromieh et al., 2015) and can be considered representative. The highest physiological tracer uptake is found in the kidneys and salivary glands and increases over time. A thin coronal slice through the kidney (Fig. 6B, upper) demonstrates strong tracer uptake in the renal cortex, leading to PSMA expression in the proximal tubules reported in so-called histopathological examination. Correspond.

The in vivo distribution of ⁶⁸ Ga-PSMA-617 (Fig. 6A, right; maximal projection 1 h pi) in volunteers pre-medicated with Tris-POC-2-PMPA was significant without further tracer accumulation over time. It revealed a decrease in renal uptake. A thin coronary slice through the kidney (Fig. 6B, bottom) demonstrates a uniform contrast of the entire renal parenchyma, but tracer accumulation was only observed in the calyx; passing through the entire nephron. Means clearance by.

Maximum uptake in renal parenchyma was reduced by 65% in pre-medicated volunteers for Tris-POC-2-PMPA compared to typical controls (SUVmax 16.5 vs. 47.5). The effect was very similar for the parotid gland (SUVmax 13.5 vs 41.2). The observed tracer uptake of Tris-POC-2-PMPA pre-medication volunteers was reduced by more than one standard deviation compared to the mean renal / parotid uptake published by Afshar-Oromieh et al., 2015. Therefore, the chance that the result was observed by chance is <5%.

Incorporation of tumors, kidneys and salivary glands in prostate cancer patients examined with ⁶⁸ Ga-PSMA-617 with and without pre-medication of Tris-POC-2-PMPA

Avid uptake of PSMA radioligand in metastases (SUVmax3.6-12.5), parotid glands (SUVmax18.2), submandibular glands (SUVmax23.1), and kidneys (SUVmax35.4) , ⁶⁸ Ga-PSMA-617 was first confirmed in a single patient by PET scan 1 hour after administration (Fig. 7, top left). At a later date, when administered in the same patient 15 minutes before injection of ⁶⁸ Ga-PSMA-617, Tris-POC-2-PMPA (10 mg, iv) reduced radioligand uptake in the submandibular gland (SUVmax10. 6), submandibular gland (SUVmax14.6), and kidney (SUVmax8.5), but had no clear effect on metastasis (SUVmax3.9-8.8) (Fig. 7, top right). By quantification as a percentage change within the subject, Tris-POC-2-PMPA reduced salivary gland and renal uptake by 37% and 76%, respectively. After pretreatment with TRIS-POC-2-PMPA, metastases showed an average change of only 3%, and some lesions did show increased uptake of ⁶⁸ Ga-PSMA-617.

TRIS-POC-2-PMPA pretreatment reduced the uptake of ¹⁷⁷ Lu-PSMA-617 in the salivary glands and kidneys of the mCRPC patient, but not in metastases.

Based on a positive diagnostic PET scan, the two mCRPC patients subsequently received TRIS-POC-2-PMPA (10 mg, iv) 15 minutes prior to infusion of ¹⁷⁷ Lu-PSMA-617 (10 mg, iv). Representative patients in the upper part of Figure 8, separation lines are diagnostic scans on the left, therapeutic scans on the right; separate summary data in the table below). Compared to historical controls from the same center (Kratochwil et al., 2016), TRIS-POC-2-PMPA pretreatment reduces and absorbs radiotherapy uptake in the parotid, submandibular, and kidney glands. Dose was delivered at 0.24, 0.5, and 0.38 Gy / GBq for Patient 1, respectively, and at 0.46, 0.44, and 0.43 Gy / GBq for Patient 2, respectively. All of these values are outside the standard deviation of historical control and represent mean dose reductions of 76%, 67%, and 48% for the parotid, submandibular, and kidney, respectively. In contrast, TRIS-POC-2-PMPA pretreatment had little or no effect on the dose to metastases. Patient 1 showed an average dose of 8.03 Gy / GBq, and Patient 2 showed an average dose of 13.15 Gy / GBq. Both of these values fall within the standard deviation of historical control and, importantly, are at or above the absorbed dose values reported to have therapeutic efficacy (Kratochwil et al., 2016). high.

Although not a dose limitation, TRIS-POC-2-PMPA was thought to moderately reduce liver exposure to ¹⁷⁷ Lu-PSMA-617 without a clear effect on splenic dose. TRIS-POC-2-PMPA also significantly reduced exposure to the lacrimal glands. One recent report predicted that the lacrimal gland was the first organ to reach a critical threshold after ¹⁷⁷ Lu-PSMA-617 therapy and receive an average effective dose of 2.82 Gy / GBq (Hohberg et al., 2016). .. This value is similar to that reported in another recent study (Scarpa et al., 2017), as well as the values obtained in the historical controls presented here. Compared to these mean control values, pretreatment with TRIS-POC-2-PMPA resulted in a dose reduction to the lacrimal gland of approximately 82%.

Other healthy organ dose measurements for historical control patients used as direct comparators in this study receive therapeutic or sub-therapeutic (sub-therapeutic) concentrations of ¹⁷⁷ Lu-PSMA-617. It is important to note that the mCRPC patient is very close to the previously reported median (Kratochwil et al., 2016; Hohberg et al., 2016; Scarpa et al., 2017; Delker et al., 2016; Fendler et al., 2017; Kabasakal et al., 2015; Kabasakal et al., 2017; Yadav et al., 2017). In the subject matter of this disclosure, the controls are the average absorbed dose to the salivary glands of 1.44 Gy / GBq (reported range: 0.72-1.90 Gy / GBq) and 0.78 Gy / GBq to the kidneys (reported range: 0.53-0.99 Gy / GBq). ), And 0.03 Gy / GBq to the red bone marrow (report range: 0.01-0.05 Gy / GBq), and can therefore be considered representative.
References

All publications, patent applications, patents, and other references mentioned herein refer to the level of skill in the art in which the subject matter of this disclosure is relevant. All publications, patent applications, patents, and other references are indicated as if each individual publication, patent application, patent, and other references were specifically and individually incorporated by reference. Incorporated here by reference to the same extent as if. Multiple patent applications, patents, and other references are referred to herein, which constitute an endorsement that any of these documents form part of the common general knowledge of the art. It will be understood that it is not something to do. If there is a conflict between this specification and any of the incorporated references, this specification (including any modifications thereof, which may be based on the incorporated references) should be controlled. The meanings of terms accepted in standard technology are used herein unless otherwise indicated. Standard abbreviations are used here for various terms.

Afshar-Oromieh A, Hetzheim H, Kratochwil C, etc. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET / CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. (The Theranostic PSMA Ligand PSMA-617: Human body distribution, dosimetry, and initial assessment of tumor lesions.) J Nucl Med. 2015 Nov (November); 56 (11): 1697-705.
Afshar-Oromieh A. et al., The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer. (The rise of PSMA ligands for the diagnosis and treatment of prostate cancer.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 57, 79s-89s (2016).
Akhtar NH, O. Pail, A. Saran, L. Tyrell, ST Tagawa, Prostate-specific membrane antigen-based therapeutics. Substances for use.) Advances in urology 2012, 973820 (2012).
Baum (Beam) RP, et al., 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. And effectiveness.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 57, 1006-1013 (2016).
Begum N. et al., The effect of total tumor volume on the biologically effective dose of tumor and kidneys for (177) Lu-labeled PSMA peptides. ((177) Lu-labeled PSMA peptides) Tumor and kidney biology Effect of total tumor volume on effective dose.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine (February 1, 2018).
Beltran H. et al., New therapies for castration-resistant prostate cancer: efficacy and safety. (New therapies for castration-resistant prostate cancer: efficacy and safety.) European urology 60, 279-290 (2011).
Benesova M. et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. (Lincolmo optimized for prostate cancer imaging and internal radiotherapy) Preclinical evaluation of tailor-made DOTA-conjugated PSMA inhibitors with Yeti.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 56, 914-920 (2015).
Benesova M., CA Umbricht, R. Schibli, C. Muller, Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile. (Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile.) .) Molecular pharmaceutics 15, 934-946 (2018).
Bodei L. et al., Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. (90Y-DOTATOC and 177Lu-DOTATATE peptide receptor radionuclides Long-term assessment of renal toxicity after therapy: the role of related risk factors.) European journal of nuclear medicine and molecular imaging 35, 1847-1856 (2008).
Bouchelouche K., B. Turkbey, PL Choyke, PSMA PET and Radionuclide Therapy in Prostate Cancer. (PSMA PET and radionuclide therapy in prostate cancer.) Seminars in nuclear medicine 46, 522-535 (2016) ..
Ceci F, Fiorentino M, Castellucci P, Fanti S. Molecular Imaging and Precision Medicine in Prostate Cancer. (Molecular Imaging and Precision Medicine in Prostate Cancer) PET clinics 2017; 12: 83-92.
Chang SS, Overview of prostate-specific membrane antigen. Reviews in urology 6 Suppl 10, S13-18 (2004).
Chatalic KL et al., Towards Personalized Treatment of Prostate Cancer: PSMA I & T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent. (PSMA I & T, a promising prostate-specific membrane antigen-targeted therapeutic agent. ) Theranostics 6, 849-861 (2016).
de Bono JS et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. (Prednisone for metastatic castration-resistant prostate cancer that progresses after docetaxel treatment. Plus cabazitaxel or mitoxantrone: a randomized open-label trial.) Lancet (London, England) 376, 1147-1154 (2010).
Delker A. et al., Dosimetry for (177) Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. ((177) Dosimetry for Lu-DKFZ-PSMA-617: of metastatic prostate cancer A new radiopharmaceutical for treatment.) European journal of nuclear medicine and molecular imaging 43, 42-51 (2016).
Donin NM, RE Reiter, Why Targeting PSMA Is a Game Changer in the Management of Prostate Cancer. (Why Targeting PSMA Makes a Big Change in Prostate Cancer Management) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 59, 177-182 (2018).
Eiber M. et al., Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 67s-76s (2017).
Fakhrejahani F., RA Madan, WL Dahut, Management Options for Biochemically Recurrent Prostate Cancer. Current treatment options in oncology 18, 26 (Fakhrejahani F., RA Madan, WL Dahut, Management Options for Biochemically Recurrent Prostate Cancer. 2017).
Fendler WP et al., Preliminary experience with dosimetry, response and patient reported outcome after 177Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer. Dosimetry after 177Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer. And preliminary experience with patient-reported results.) Oncotarget 8, 3581-3590 (2017).
Fendler WP, K. Rahbar, K. Herrmann, C. Kratochwil, M. Eiber, (177) Lu-PSMA Radioligand Therapy for Prostate Cancer. ((177) Lu-PSMA Radioligand Therapy for Prostate Cancer. .) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1196-1200 (2017).
Freiberger C. et al., Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer --focus on overall survival. Long-term prognostic significance of rising PSA levels after radiation therapy for localized prostate cancer- Focus on overall survival.) Radiation oncology (London, England) 12, 98 (2017).
Gaertner FC et al., Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. (Uptake of PSMA ligand in normal tissues depends on the tumor volume of prostate cancer patients.) Oncotarget 8, 55094 -55103 (2017).
Haberkorn U, Eder M, Kopka K, Babich JW, Eisenhut M. New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy. New Strategy for Cancer: Prostate Specific Membrane Antigen (PSMA) Ligand for Diagnosis and Treatment.) Clin Cancer Res (Clinical Cancer Research) 2016; 22: 9-15.
Haberkorn U., F. Giesel, A. Morgenstern, C. Kratochwil, The Future of Radioligand Therapy: alpha, beta, or Both? (Future of radioligand therapy: alpha, beta, or both?) ?) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1017-1018 (2017).
Halabi S. et al., Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. (Halabi), et al., Overall survival in initial chemotherapy for patients with metastatic castration-resistant prostate cancer. Updated Prognostic Model for Prediction.) Journal of clinical oncology: official journal of the American Society of Clinical Oncology 32, 671-677 (2014).
Han M. et al., Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. Biochemical (prostate-specific antigen) recurrence after radical prostatectomy for clinically localized prostate cancer. Probability.) The Journal of urology 169, 517-523 (2003).
Hofman MS et al., Lutetium-177 PSMA (LuPSMA) theranostics phase II trial: efficacy, safety and QoL in patients with castrate-resistant prostate cancer treated with LuPSMA. (Lutetium-177 PSMA (LuPSMA) seranostic phase II trial : Efficacy, safety and quality of life in patients with castration-resistant prostate cancer treated with LuPSMA.). Annals of Oncology 28, Suppl 5 (2017).
Hohberg M. et al., Lacrimal Glands May Represent Organs at Risk for Radionuclide
Therapy of Prostate Cancer with [(177) Lu] DKFZ-PSMA-617. (The lacrimal gland may represent an organ at risk for radionuclide treatment of prostate cancer with [(177) Lu] DKFZ-PSMA-617. .) Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 18, 437-445 (2016).
I. Endocyte. (End site) (2018).
Israeli RS, CT Powell, JG Corr, WR Fair, WD Heston, Expression of the prostate-specific membrane antigen. (Expression of prostate-specific membrane antigen) Cancer research 54, 1807-1811 (1994).
Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry. (Lu-177- in patients with castration-resistant prostate cancer) PSMA-617 Prostate-specific membrane antigen inhibitor therapy: stability, biodistribution and dosimetry.) Molecular imaging and radionuclide therapy 26, 62-68 (2017).
Kabasakal L. et al., Pre-therapeutic dosimetry of normal organs and tissues of (177) Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. (Patients with castration-resistant prostate cancer) (177) Lu-PSMA-617 Prostate-Specific Membrane Antigen (PSMA) Inhibitor Dosimetry of Normal Organs and Tissues Before Treatment.) European journal of nuclear medicine and molecular imaging 42, 1976-1983 (2015).
Kantoff PW et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine 363, 411-422 (2010).
Kasperzyk JL, Finn SP, Flavin R et al., Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer. (Expression and fatality of prostate-specific membrane antigen protein in tumor tissue) Risk of Prostate Cancer.) Cancer Epidemiol Biomarkers Prev 2013; 22: 2354-63.
Kiess AP et al., (2S) -2- (3- (1-Carboxy-5- (4-211At-Astatobenzamido) Pentyl) Ureido)-Pentanedioic Acid for PSMA-Targeted alpha-Particle Radiopharmaceutical Therapy. ((2S) ) -2- (3- (1-carboxy-5- (4-211At-Astatobenzamide) Pentyl) Ureid)-Penthanic Acid PSMA-Targeted Alpha-Particle Radiopharmaceutical Treatment.) Journal of nuclear medicine: official publication , Society of Nuclear Medicine 57, 1569-1575 (2016).
Klein Nulent TJW et al., Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET / CT. (Physiology of PSMA ligand in mixed glands of salivary glands and head and neck on PET / CT) Regional distribution.) Oral surgery, oral medicine, oral pathology and oral radiology, (2018).
Kopka K., M. Benesova, C. Barinka, U. Haberkorn, J. Babich, Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular- Weight Theranostic Radiotracers. (Glu-ureid-based inhibitor of prostate-specific membrane antigens: lessons learned during the development of a new class of low molecular weight theranostic radiotracers.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 17s -26s (2017).
Kratochwil C. et al., PMPA for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer. (PMPA for renal protection in PSMA-targeted radionuclide therapy for prostate cancer) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 56, 293-298 (2015).
Kratochwil C. et al., PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. nuclear medicine: official publication, Society of Nuclear Medicine 57, 1170-1176 (2016).
Kratochwil C. et al., Targeted Alpha Therapy of mCRPC with (225) Actinium-PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control. ((225) Targeted alpha therapy for mCRPC with actinium-PSMA-617) : Swimmer plot analysis suggests efficacy for duration of tumor control.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine, (2018).
Kratochwil C. et al., Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA-617: Dosimetry estimate and empirical dose finding. ) Journal of nuclear medicine: official publication, Society of Nuclear Medicine, (2017).
Kratochwil C. et al., Targeted alpha therapy of mCRPC: Dosimetry estimate of (213) Bismuth-PSMA-617. (MCRPC targeted alpha therapy of mCRPC: (213) Bismuth-PSMA-617 dosimetry estimate of nuclear.) medicine and molecular imaging 45, 31-37 (2018).
Kratochwil C. et al., Targeted alpha-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225) Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding. Targeted alpha therapy for cancer: Dosimetric estimates and empirical dose findings.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1624-1631 (2017).
Kratochwil C., A. Afshar-Oromieh, K. Kopka, U. Haberkorn, FL Giesel, Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnostics and Therapy for Prostate Cancer. (Current status of prostate-specific membrane antigen targeting in nuclear medicine: clinical interpretation of chelating agents containing prostate-specific membrane antigen ligands for diagnosis and treatment of prostate cancer.) Seminars in nuclear medicine 46. , 405-418 (2016).
Kwekkeboom D., Perspective on 177Lu-PSMA Therapy for Metastatic Castration-Resistant Prostate Cancer. Journal of nuclear medicine: official publication, Society of nuclear medicine: official publication, Society of nuclear medicine: official publication, Society of nuclear medicine: official publication, Society of Nuclear Medicine 57, 1002-1003 (2016).
Liu H. et al., Constitutive and antibody-induced internalization of prostate-specific membrane antigen. Cancer research 58, 4055-4060 (1998).
Lutje S. et al., PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status. (PSMA Ligand for Radionuclide Imaging and Treatment of Prostate Cancer: Clinical Status.) Theranostics 5, 1388-1401 (2015) ..
Majer P. et al., Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). ) Discovery of an orally administrable prodrug.) Journal of medicinal chemistry 59, 2810-2819 (2016).
Maurer T., M. Eiber, M. Schwaiger, JE Gschwend, Current use of PSMA-PET in prostate cancer management. (Current use of PSMA-PET in prostate cancer management.) Nature reviews. Urology 13, 226-235 (2016).
Moreira DM et al., Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. (Predicting the time from metastasis to overall survival of castration-resistant prostate cancer: results from SEARCH.) Clinical genitourinary cancer 15, 60-66.e62 (2017).
Morris MJ et al., Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. (Progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 Results.) Journal of clinical oncology: official journal of the American Society of Clinical Oncology 33, 1356-1363 (2015).
Nedelcovych M. et al., Enhanced Brain Delivery of 2- (Phosphonomethyl) pentanedioic Acid Following Intranasal Administration of Its gamma-Substituted Ester Prodrugs. (Intranasal gamma-substituted ester prodrugs of 2- (phosphonomethyl) pentanomethyl) Enhanced brain delivery of 2- (phosphonomethyl) pentandiic acid after administration.) Molecular pharmaceutics 14, 3248-3257 (2017).
O'Keefe DS, DJ Bacich, WD Heston, Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene. (Prostate-specific membrane antigen (PSMA) vs. prostate Comparative analysis of specific membrane antigen-like genes.) The Prostate 58, 200-210 (2004).
Omlin A. et al., Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. In a cohort of study participants with metastatic castration-resistant prostate cancer. Improvements indicate the need for an updated prognostic nomogram.) European urology 64, 300-306 (2013).
Parker C. et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. (Survival in alpha emitter radium-223 and metastatic prostate cancer.) The New England journal of medicine 369, 213-223 (2013).
Perner S, Hofer MD, Kim R, et al., Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. (Expression of prostate-specific membrane antigen as a predictor of prostate cancer progression) Hum Pathol (Human Pathology) 2007; 38: 696-701.
Petrylak DP et al., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. (Comparison of docetaxel and estramustine with mitoxantrone and prednisone for advanced refractory prostate cancer.) The New England journal of medicine 351, 1513-1520 (2004).
Pillai MR, Nanabala R, Joy A, Sasikumar A, Russ Knapp FF. Radiolabeled enzyme inhibitors and binding agents targeting PSMA: Effective theranostic tools for imaging and therapy of prostate cancer. (Radiolabeling Enzyme Inhibitors and Binders Targeting PSMA: Effective Theranostic Tools for Imaging and Treatment of Prostate Cancer.) Nucl Med Biol 2016; 43: 692 -720.
Rahbar K. et al., German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. (German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in patients with advanced prostate cancer.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 85-90 (2017).
Rahbar K., H. Ahmadzadehfar, M. Boegemann, (177) Lu-PSMA-617 radioligand therapy in mCRPC: ready for phase III trial? ((177) Lu-PSMA-617 in mCRPC Radioligand therapy: Are you ready for the Phase III trial?) European journal of nuclear medicine and molecular imaging 45, 513-514 (2018).
Ramadan (Ramadan) WH, WK Kabbara (Kabbalah), HS Al Basiouni Al Masri (Al Basiouni Al Masri), Enzalutamide for patients with metastatic castration-resistant prostate cancer. (For patients with metastatic castration-resistant prostate cancer Enzalutamide.) OncoTargets and therapy 8, 871-876 (2015).
Ristau BT, DS O'Keefe, DJ Bacich, The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. (Prostate-specific membrane antigens: lessons learned from 20 years of research and the present Clinical significance of.) Urology oncology 32, 272-279 (2014).
Saad F. et al., The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). (2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC).) Canadian Urological Association journal = Journal de l'Association des urologues du Canada 9, 90-96 (2015).
Scarpa L. et al., The (68) Ga / (177) Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates. (68) in PSMA targeting of castration-resistant prostate cancer. Ga / (177) Lu diagnostic concept: Correlation between SUVmax value and absorbed dose estimate.) European journal of nuclear medicine and molecular imaging 44, 788-800 (2017).
Schwarzenboeck SM et al., PSMA Ligands for PET Imaging of Prostate Cancer. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 58, 1545-1552 (2017) ..
Silver DA, I. Pellicer, WR Fair, WD Heston, C. Cordon-Cardo, Prostate-specific membrane antigen expression in normal and malignant human tissues. (In normal and malignant human tissues. Prostate-specific membrane antigen expression.) Clinical cancer research: an official journal of the American Association for Cancer Research 3, 81-85 (1997).
Taieb D. et al., PSMA-Targeted Radionuclide Therapy and salivary gland toxicity: why does it matter? (PSMA-Targeted Radionuclide Therapy and salivary gland toxicity: why is it important?) Journal of nuclear medicine: official publication, Society of Nuclear Medicine , (2018).
Torre LA et al., Global cancer statistics, 2012. CA: a cancer journal for clinicians 65, 87-108 (2015).
Valkema R. et al., Long-term follow-up of renal function after peptide receptor radiation therapy with (90) Y-DOTA (0), Tyr (3) -octreotide and (177) Lu-DOTA (0), After peptide receptor radiotherapy with Tyr (3) -octreotate. ((90) Y-DOTA (0), Tyr (3) -octreotide and (177) Lu-DOTA (0), Tyr (3) -octreotate. Long-term follow-up of renal function.) Journal of nuclear medicine: official publication, Society of Nuclear Medicine 46 Suppl 1, 83s-91s (2005).
Virgolini I., C. Decristoforo, A. Haug, S. Fanti, C. Uprimny, Current status of theranostics in prostate cancer. Current status.) European journal of nuclear medicine and molecular imaging, (2017).
Virgolini I., C. Decristoforo, A. Haug, S. Fanti, C. Uprimny, Current status of theranostics in prostate cancer. (European journal of nuclear medicine and molecular imaging 45, 471- 495 (2018).
von Eyben (von Eyben) FE et al., Third-line treatment and (177) Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. ) Lu-PSMA Radioligand Therapy: Systematic Review.) European journal of nuclear medicine and molecular imaging, (2017).
Yadav MP et al., Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. 177Lu-DKFZ-PSMA-617 Post-treatment dosimetry.) Nuclear medicine communications 38, 91-98 (2017).
Yordanova A. et al., The impact of repeated cycles of radioligand therapy using [(177) Lu] Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer. (, [(177) Lu] Lu- Effect of repeated cycles of radioligand therapy using PSMA-617 on renal function in patients with hormone-resistant metastatic prostate cancer.) European journal of nuclear medicine and molecular imaging 44, 1473-1479 (2017).
Zechmann CM et al., Radiation dosimetry and first therapy results with a (124) I / (131) I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. (Targeting PSMA for prostate cancer treatment) (124) I / (131) I-labeled small molecule (MIP-1095) radiation dosimetry and results of initial treatment.) European journal of nuclear medicine and molecular imaging 41, 1280-1292 (2014).
Zumsteg ZS et al., The natural history and predictors of outcome following biochemical relapse in the dose escalation era for prostate cancer patients undergoing definitive external beam radiotherapy. Prediction of natural development and outcome after biochemical recurrence at the time of increase.) European urology 67, 1009-1016 (2015).

Although the subject matter of the above items has been described in some detail as examples and examples for the purpose of clarifying understanding, it is in the present art that certain modifications and modifications can be practiced within the scope of the appended claims. It will be understood by a skilled person.

Having described the subject matter of the present disclosure in general terms in this way, the accompanying drawings will be referred to next, but they are not necessarily drawn to scale and are as follows:
It is shown that the Tris-POC-2-PMPA prodrug delivered significantly higher 2-PMPA concentrations to the kidneys of nude mice. Compared to equimolar doses of 2-PMPA, Tris-POC-2-PMPA (5 mg / kg, ip) increased 2-PMPA levels in the kidney by more than 20-fold. 2A and 2B show that, in contrast to the 2-PMPA prodrugs of the present disclosure, a similar prodrug of the alternative urea-based PSMA ligand, ZJ-43, compared to the parental administration of ZJ-43. (Fig. 2A), showing no increased distribution to mouse kidneys or salivary glands (Fig. 2B). 3A and 3B show Tris-POC-2-PMPA treatment (Figure 3A) compared to equimolar 2-PMPA treatment in prostate cancer tumor-bearing mice. It is shown that 3B) results in significantly increased renal and salivary gland delivery of 2-PMPA, and improved kidney: tumor and saliva: tumor ratio. Tail veins of either 2-PMPA or Tris-POC-2-PMPA (3 mg / kg or molar equivalent, iv) to NSG mice with subcutaneous xenografts of human C4-2 prostate cancer cells Concentrations of 2-PMPA in the prostate, tumor, salivary gland, and kidney were measured at multiple time points after dosing. Figures 4A, 4B, 4C, and 4D are presented as baseline PET imaging (maximum intensity projections) of nontumor-bearing mice 1 hour after injection of 20 MBq of ⁶⁸ Ga-PSMA-617. ) (Fig. 4A) and quantification of renal uptake by mSUV (Fig. 4C). The same animals were reimaging one hour after the subsequent injection of Tris-POC-2-PMPA (0.5 mg / kg BW) (Fig. 4B). Tracer concentrations were then quantified in the kidney by mSUV (Fig. 4D). Figures 5A, 5B, 5C, and 5D show kidneys and mSUV-based kidneys and mSUV-carrying mice carrying LNCaP tumor xenografts (left shoulder) 1 hour after injection of ⁶⁸ Ga-PSMA-617. Quantification of tumor uptake (Fig. 5C) is shown. The same animals were reimaged an additional hour after subsequent injections of different doses of Tris-POC-2-PMPA (or sarin (salt solution) as a control) (Fig. 5B), followed by quantified tumor and renal uptake. (Fig. 5D).

The subject matter of this disclosure demonstrates the effectiveness of this approach. For example, in mice carrying prostate tumors, administration of the 2-PMPA prodrug prior to administration of the PSMA radioligand successfully replaced the binding of radioligands in the kidneys and salivary glands, but preserved tumor uptake. Was done. Therefore, the 2-PMPA prodrugs of the present disclosure are clinically used as pretreatment agents to improve the specificity of PSMA-targeted imaging (also referred to as imaging) agents and radiotherapy and reduce their toxicity. It has the potential to be used as a target.

Therefore, the subject matter of the present disclosure provides unexpected insights into PSMA small molecule inhibitors with enhanced accumulation in non-cancerous tissues (eg, kidney, lacrimal gland, and salivary gland). Animal data indicate that the 2-PMPA prodrugs of the present disclosure can be used in combination with PSMA-targeted imaging or radiation therapy to reduce non-selective and potential dose-limiting toxicity, respectively.

Claims (45)

A method for preventing or reducing exposure to prodrug-specific membrane antigen (PSMA) -targeted imaging or therapeutic agents in off-target non-cancerous tissue of 2- (phosphonomethyl) pentanedioic acid (2-PMPA). A method comprising administering a prodrug to a subject treated with a PSMA targeting agent in an amount effective to prevent or reduce the binding of the PSMA targeting agent to off-target non-cancerous tissue. 2-PMPA prodrugs include compounds of formula (I) or formula (II):
During the ceremony:
Each R ₁ , R ₂ , R ₃ , and R ₄ are H, Alkyl, Ar,-(CR ₅ R ₆ ) _n -Ar,-(CR ₅ R ₆ ) _n -OC (= O) -R ₇ , -(CR ₅ R ₆ ) _n -C (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OC (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OR ₇ ,-(CR ₅ R ₆ ) CR ₅ R ₆ ) _n -O-[(CR ₅ R ₆ ) _n -O] _m -R ₇ ,-(CR ₅ R ₆ ) _n -Ar-OC (= O) -R ₇ , -Ar-C ( = O) -O- (CR ₅ R ₆ ) _n -R ₇ ,-(CR ₅ R ₆ ) _n -NR ₈ R ₉ , and-(CR ₅ R ₆ ) _n -C (= O) -NR ₈ R Selected independently from the group of ₉ ;
During the ceremony:
n is an integer from 1 to 20;
m is an integer from 1 to 20;
Each R ₃ 'and R _4' are independently H or alkyl;
Each R ₅ and R ₆ was selected independently from the group consisting of H, alkyl, and alkylaryl;
Each R ₇ is linear or branched alkyl independently;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and
The method of claim 1, wherein R ₈ and R ₉ are independently H or alkyl; as well as pharmaceutically acceptable salts thereof. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is
The method of claim 2. The compound of formula (I) is

The method of claim 2. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compound of formula (I) is
The method of claim 2. The compounds of formula (I) are:
The method of claim 2, which is selected from the group consisting of. The compound of formula (II) is
The method of claim 2. The compound of formula (II) is
The method of claim 2. The method of claim 1, wherein the 2-PMPA prodrug is administered in combination with PSMA-targeted imaging or a therapeutic agent. The method of claim 29, wherein the 2-PMPA prodrug is administered to the subject prior to PSMA-targeted imaging or therapeutic agent application. The method of claim 29, wherein the 2-PMPA prodrug is administered to the subject at the same time as the PSMA-targeted imaging or therapeutic agent. The method of claim 1, wherein the off-target tissue is in an organ selected from the group consisting of kidneys, lacrimal glands, and salivary glands. The method of claim 1, wherein the PSMA-targeted imaging or therapeutic agent is selected from the group consisting of PSMA-11, PSMA-617, and PSMA I & T. A method that involves giving a patient a therapeutically effective amount of a 2-PMPA prodrug in reducing salivary gland damage in a patient receiving PSMA-targeted therapy for cancer. The method of claim 34, wherein salivary gland injury causes side effects selected from the group consisting of dry mouth, concentrated saliva, decreased saliva, stomatitis, hoarseness, dysphagia, loss of taste, and combinations thereof. A method that involves giving a patient a therapeutically effective amount of a 2-PMPA prodrug in reducing renal damage in a patient receiving PSMA-targeted therapy for cancer. 2-PMPA prodrugs include compounds of formula (I) or formula (II):
During the ceremony:
Each R ₁ , R ₂ , R ₃ , and R ₄ are H, Alkyl, Ar,-(CR ₅ R ₆ ) _n -Ar,-(CR ₅ R ₆ ) _n -OC (= O) -R ₇ , -(CR ₅ R ₆ ) _n -C (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OC (= O) -OR ₇ ,-(CR ₅ R ₆ ) _n -OR ₇ ,-(CR ₅ R ₆ ) CR ₅ R ₆ ) _n -O-[(CR ₅ R ₆ ) _n -O] _m -R ₇ ,-(CR ₅ R ₆ ) _n -Ar-OC (= O) -R ₇ , -Ar-C ( = O) -O- (CR ₅ R ₆ ) _n -R ₇ ,-(CR ₅ R ₆ ) _n -NR ₈ R ₉ , and-(CR ₅ R ₆ ) _n -C (= O) -NR ₈ R Selected independently from the group of ₉ ;
During the ceremony:
n is an integer from 1 to 20;
m is an integer from 1 to 20;
Each R ₃ 'and R _4' are independently H or alkyl;
Each R ₅ and R ₆ was selected independently from the group consisting of H, alkyl, and alkylaryl;
Each R ₇ is linear or branched alkyl independently;
Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and
The method of any one of claims 34-36, wherein R ₈ and R ₉ are independently H or alkyl, respectively; and include pharmaceutically acceptable salts thereof. 2-PMPA prodrugs are:
The method of any one of claims 34-37, selected from the group consisting of. PSMA-targeted imaging or therapeutic agents include 117Lu-PSMA-617, 131I-MIP-1095, 177Lu-PSMA-I & T, 177Lu-PSMA-R2, 225Ac-PSMA-617, 227Th-PSMA-ADC, CTT1403, CTT1700, The method of any one of claims 34-38, selected from the group consisting of 68Ga-PSMA-11, 18F-DCFPyL, CTT1057, 68Ga-PSMA-R2, and 68Ga-PSMA-617. The method of any one of claims 34-39, wherein the PSMA targeted therapeutic substance is a radiotherapeutic substance applied in a cumulative amount from about 3 GBq to about 100 GBq. The method of claim 40, wherein the PSMA-targeted radiotherapeutic material is applied in cumulative amounts from about 52 GBq to about 100 GBq. The method of any one of claims 34-41, wherein the PSMA-targeted therapeutic substance and 2-PMPA prodrug are applied for about 1 to about 15 treatment cycles. The method of claim 42, wherein the PSMA-targeted therapeutic agent and 2-PMPA prodrug are applied for about 6 to about 15 treatment cycles. The method of any one of claims 34-43, wherein the patient has not previously been treated for cancer. The method of any one of claims 34-44, wherein the cancer is prostate cancer.